Cabotegravir

  • Abbreviation: CAB
    Antiretroviral Subclass:
    Integrase inhibitors

Background

  • U.S. Manufacturer:
    ViiV Healthcare

    Approval

    Cabotegravir (CAB) is an integrase inhibitor that was approved by the U.S. Food and Drug Administration (FDA) in 2021 for use in adults with HIV infection. It is the first integrase inhibitor to be available as an extended-release injectable formulation.  Extended-release injectable cabotegravir was approved by the FDA in 2021 for use as pre-exposure prophylaxis (PrEP); see Special Uses, below.

    For treatment of HIV, cabotegravir was approved specifically to be used in combination with injectable rilpivirine (RPV). Injectable extended-release cabotegravir + rilpivirine is indicated as a replacement (switch) regimen for treatment of persons with virologic suppression on antiretroviral therapy and whose virus has no resistance to cabotegravir or rilpivirine. The combination is marketed in the United States under the brand name Cabenuva.

    Approval of cabotegravir for HIV treatment was based largely on two randomized, double-blind Phase 3 studies in adults showing that a switch from 3-drug oral antiretroviral therapy to long-acting injectable cabotegravir + rilpivirine resulted in rates of viral suppression comparable to those achieved with standard oral regimens.(1),(2)

    Approval of cabotegravir for PrEP was based on two randomized, double-blind Phase 3 studies showing long-acting injectable cabotegravir was more effective than daily oral tenofovir disoproxil fumarate (TDF) + emtricitabine (FTC) in preventing HIV infection.(3),(4)

Formulations and Dosing

  • Cabotegravir is available primarily as an extended-release injectable formulation, co-packaged with extended-release injectable rilpivirine (Cabenuva; for treatment of HIV) or as a single agent (Apretude; for pre-exposure prophylaxis). It also is available in an oral formulation (Vocabria) to be used for a short time (eg, up to 1 month), either for an initial (lead-in) period to assess tolerability to cabotegravir or as a bridge between cabotegravir injections in the setting of a planned delay between injections.

    Adult Dosing

    Dosage Formulation Notes
    30 mg PO daily Tablet

    Available for short-term use in certain circumstances (eg, oral lead-in period before starting injectable CAB or during expected delays in CAB injections). 
    CAB 600 mg IM injection (coadministered with RPV 900 mg) Subcutaneous Injection

    1st IM dose on last day of oral lead-in period

    CAB 600 mg IM injection (coadministered with RPV 900 mg) Subcutaneous Injection

    Give 2nd IM dose of CAB/RPV 600/900 mg 1 month after initial injection, then every 2 months
    CAB 400 mg IM injection (coadministered with RPV 600 mg) Subcutaneous Injection

    Start  CAB/RPV 400/600 mg 1 month after initial CAB/RPV 600/900 mg injection, then every 1 month
    CAB 600 mg IM monthly x 2 doses, then every 2 months Subcutaneous Injection

    1st IM dose on last day of oral lead-in period

    2nd IM dose 1 month after initial injection; then every 2 months

    • There are no food restrictions.
    • No dosage adjustment is required is required for patients with creatinine clearance ≥30 mL/min. Persons with creatinine clearance 15 to <30 mL/min, should be monitored for adverse effects. No data are available for use in persons with creatinine clearance <15 mL/min.
    • No dosage adjustment is required is required for persons with mild-moderate liver disease (Child-Pugh A or B); not studied in persons with severe (Child-Pugh Class C) disease.
    • Cabotegravir has not been studied in pregnant persons.
    • Cabotegravir interacts with other medications; dosage adjustments may be required and certain combinations are contraindicated. For more information about drug interactions, see "Interactions with Other Drugs" below and refer to the Database of Antiretroviral Drug Interactions.
    • Consult product labeling for detailed dosing information.

    Abbreviations: CAB: cabotegravir. IM: intramuscular. PO: by mouth. QD = Once daily. RPV: rilpivirine

    Pediatric Dosing

    Age Dosage Formulation Weight
    < 18 years Not approved    
      Adult dosing   ≥35 kg

    Formulations

    oval white table with "SV CTV" imprint
    ViiV Connect
    30 mg
    Image
    oval white table with "SV CTV" imprint
    label of initiation kit
    Cabenuva
    400 mg
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    label of initiation kit
    cabenuva label
    600 mg
    Image
    cabenuva label

Coformulations

Clinical Use

  • Initial vs Subsequent Therapy
    Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services (DHHS) do not include the cabotegravir among the "recommended initial regimens for most people with HIV."


    For treatment of HIV, cabotegravir has been studied only in persons with viral suppression on a 3-drug oral antiretroviral regimen and no known viral resistance to integrase inhibitors.


    Two Phase 3 double-blind studies (described above in "Approval") randomized subjects to switch to the combination of extended-release intramuscular cabotegravir + an extended-release intramuscular formulation of the nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine or to continue their daily oral regimen.  In the FLAIR study, ART-naïve individuals were initially treated with daily oral dolutegravir/abacavir/lamivudine.  After 20 weeks, those with viral suppression were randomized to switch to cabotegravir + rilpivirine injections given every 4 weeks (CAB 400 mg + RPV 600 mg) after a 4-week trial period of daily oral cabotegravir + rilpivirine, or to continue daily oral dolutegravir/abacavir/lamivudine. After 48 weeks, by FDA snapshot analysis, 93.6% of the cabotegravir + rilpivirine group and 93.3% of the oral therapy group maintained HIV RNA <50 copies/mL (adjusted difference, 0.4 percentage points; 95% confidence interval for the difference, -2.8-2.1); results met criteria for noninferiority of the injectable regimen. In the ATLAS study, subjects on a variety of standard 3-drug oral antiretroviral regimens were randomized to switch to every-4-week cabotegravir + rilpivirine injections (again, after a 4-week lead-in period of oral cabotegravir + rilpivirine) or to continue their oral regimen. After 48 weeks, by FDA snapshot analysis, 92.5% of the cabotegravir + rilpivirine group and 95.5% of the oral therapy group maintained HIV RNA <50 copies/mL (adjusted difference, -3.0 percentage points; 95% CI for the difference -6.7-0.7); results met criteria for noninferiority of long-acting cabotegravir + rilpivirine.(2)


    A Phase 3b open-label study (ATLAS-2M) compared the efficacy of two different dosing intervals of long-acting intramuscular cabotegravir + rilpivirine, either every 4 weeks or every 8 weeks.Study subjects had been on a stable first or second antiretroviral therapy regimen with virologic suppression for at least 6 months, had no history of virologic failure, and no known viral resistance to integrase inhibitors or rilpivirine; some entered directly from the ATLAS study described above and were already receiving long-acting cabotegravir + rilpivirine every 4 weeks. All were randomized to receive cabotegravir + rilpivirine either every 4 weeks (cabotegravir 400 mg + rilpivirine 600 mg) or every 8 weeks (cabotegravir  600 mg + rilpivirine 900 mg); subjects who had not previously received cabotegravir + rilpivirine were initially given oral cabotegravir and rilpivirine for 4 weeks to assess tolerability before beginning injections. At week 48, 93% of the every-4-week group and 94% of the every-8-week treatment group maintained HIV RNA <50 copies/mL (adjusted treatment difference in proportions, 0.8; 95% confidence interval for the difference -2.1-3.7); the results met criteria for noninferiority of the every 8 week dosing strategy. Confirmed virologic failure was seen in 2 of the 523 in the 4-week group and in 8 of the 522 subjects in the 8-week group. (6)
    Cabotegravir has not been studied in subsequent therapy in persons whose HIV virus has mutations that confer resistance to integrase inhibitors.


    Cabotegravir also can be used as pre-exposure prophylaxis, to prevent HIV infection - see Special Uses, below. <<link>>

    Interactions with Other Drugs

    Cabotegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A9.  Other medications that induce these enzymes can substantially reduce plasma concentrations of cabotegravir and should not be given concurrently; these include the antimycobacterial drugs rifampin and rifapentine; the antiseizure drugs carbamazepine, phenytoin, and phenobarbital; and the herb and St. John's wort. Rifabutin cannot be given with extended release cabotegravir + rilpivirine, and dosage adjustment of cabotegravir is required if rifabutin is given concurrently with the extended-release preexposure prophylaxis formulation of cabotegravir.(7),(8)

    Polyvalent cations (e.g., aluminum, calcium, iron, and magnesium cations), including those contained in some antacids, laxatives, buffered medications, and mineral supplements, may interfere with gastrointestinal absorption of oral cabotegravir. Polyvalent cations should be taken ≥2 hours before or ≥4 hours after cabotegravir.(8)

    For treatment of HIV, cabotegravir is coadministered with rilpivirine, which has other significant drug-drug interactions (see  Rilpivirine ARV profile – link)

    Information on drug interactions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated.

    Resistance

    Resistance to cabotegravir is associated with the selection of 1 or more resistance mutations, but the cabotegravir resistance profile has not been characterized fully. In the Phase 3 clinical studies, virologic failure of cabotegravir + rilpivirine was associated with a number of emergent integrase mutations, including T97A, G140R, Q148R, N155H, and R263K. In the PrEP study HPTN 083, emergent integrase resistance mutations in subjects who were infected with HIV while taking cabotegravir (or who had undetected HIV before starting cabotegravir) included E138A/K, G140A/S, Q148K/R, and R263K. Phenotypic analysis showed reduced susceptibility to cabotegravir if these mutations were present, particularly with certain combinations. Additionally, in most cases of failure of cabotegravir + rilpivirine, multiple emergent rilpivirine-associated NNRTI mutations were also present. (1),(2),(3),(5),(6),(7)

    The HIV subtype A1 and the presence of the integrase polymorphism L74I at baseline have been associated with virologic failure and emergent resistance in the Phase 3 treatment studies, but the significance of these has not been fully investigated. (1),(2),(5)

    Implications of cabotegravir resistance for treatment with other antiretrovirals

    In the Phase 3 studies described above (see Use in Initial vs Subsequent Therapy), emergent cabotegravir-related resistance mutations resulted in high-level phenotypic resistance to elvitegravir and raltegravir and low-level resistance to bictegravir and dolutegravir, but no clinical studies have evaluated the efficacy of other integrase inhibitors when used after failure of cabotegravir-containing therapy.(1),(2),(3),(5),(6),(7)

    Cabotegravir mutations are not expected to affect sensitivity to other classes of antiretroviral agents.

    Implications of resistance to other antiretrovirals for treatment with cabotegravir

    Data on the effects of baseline integrase resistance mutations on cabotegravir efficacy are limited, but resistance associated with previous exposure to other integrase inhibitors may affect the efficacy of cabotegravir. In in vitro studies, a number of integrase inhibitor-associated resistance mutations reduced susceptibility to cabotegravir; these include E138A/D, Q148H/K/R, G150S, and N155H. The highest levels of resistance were seen with certain combinations of mutations, especially E138K + Q148K and Q148R + N155H. To date there have been no clinical studies of cabotegravir in persons whose HIV virus has preexisting integrase inhibitor-associated mutations.

    Resistance mutations selected by other classes of antiretrovirals are not expected to contribute to bictegravir resistance.

    Special Considerations:  <<new header, just for this drug>>

    After intramuscular injection, extended-release cabotegravir (as well as extended-release rilpivirine) remains in bloodstream of recipients for many months as it is slowly eliminated from the body. Sub-therapeutic levels of cabotegravir (and rilpivirine) may be present for 12 months or longer. If cabotegravir is stopped, or If doses are delayed, alternative therapy should be started to prevent HIV rebound and development of resistance to cabotegravir. 

    Special Uses

    Pre-Exposure Prophylaxis

    In 2021, the FDA approved long-acting intramuscular cabotegravir for use as PrEP by adults and adolescents (weight ≥35 kg) at risk of HIV infection. In the United States, injectable cabotegravir for PrEP use is marketed as Apretude.  For PrEP, cabotegravir is used as a single agent, given intramuscularly every 2 months (after 2 initial doses given 4 weeks apart). It is to be used only for persons who are tested and confirmed to be HIV uninfected.

    Two large randomized double-blind controlled studies in HIV-uninfected individuals compared the efficacy of monthly cabotegravir injections with that of daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). The first was in men who have sex with men and transgender women (HPTN 083) and the other in cisgender women (HPTN 084); all subjects were at risk for HIV infection. In both studies, injectable cabotegravir was more effective than daily oral TDF/FTC in preventing HIV infection: risk of HIV infection in the cabotegravir recipients compared with TDF/FTC recipients was 66% lower in HPTN 083 and 88% lower in HPTN 084. (3),(4),(9)

    PrEP should be used in conjunction with other prevention strategies and adherence support. Regular ongoing HIV testing is required to identify persons who become infected with HIV while on PrEP; cabotegravir is not sufficient as treatment for persons who develop HIV infection, and in persons with HIV infection, its use risks the development of resistance to the antiretroviral agents. As indicated above (Special Considerations), cabotegravir may persist in the bloodstream for months after an injection. If cabotegravir PrEP is stopped or if doses are delayed, an alternative prevention method (eg, oral PrEP) should be started to prevent HIV in persons at risk of HIV infection (and to prevent cabotegravir-related resistance in persons who become infected with HIV in the setting of waning levels of cabotegravir).

Resources and Links

Assistance Programs: ViiV Connect