U.S. Food and Drug Administration (FDA)-Approved Indications

Cabenuva is a 2-drug co-packaged product of cabotegravir, a human immunodeficiency virus type-1 (HIV-1) integrase strand transfer inhibitor (INSTI), and rilpivirine, an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI). Cabotegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Rilpivirine is a diarylpyrimidine NNRTI of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β, and γ (ViiV, 2022).

Cabenuva carries the following warnings and precautions:

The most common adverse reactions (Grades 1 to 4) observed in 2% or more of subjects receiving Cabenuva included injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.

Because Cabenuva is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Drugs that induce uridine diphosphate glucuronosyltransferase (UGT)1A1 or cytochrome P450 (CYP)3A4 may decrease the plasma concentrations of the components of Cabenuva. Cabenuva should be used with caution in combination with drugs with a known risk of Torsade de Pointes.

Per the Prescribing Information, there are insufficient human data on the use of Cabenuva during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. While there are insufficient human data to assess the risk of neural tube defects (NTDs) with exposure to Cabenvua during pregnancy, NTDs were associated with dolutegravir, another integrase inhibitor. Thus, healthcare providers need to discuss the benefit-risk of using Cabenuva with individuals of childbearing potential or during pregnancy. Lower exposures with oral rilpivirine were observed during pregnancy. Viral load should be monitored closely if the patient remains on Cabenuva during pregnancy.Cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of Cabenuva; therefore, consideration should be given to the potential for fetal exposure during pregnancy (ViiV, 2022).

Per the updated label, the safety and effectiveness of Cabenuva have been established in adolescents aged 12 to younger than 18 years and weighing at least 35 kg, which is supported by clinical trial in adults and the ongoing Phase 1 / 2 multicenter, open-label, non-comparative MOCHA (NCT03497676) trial in adolescents. The safety, efficacy, and pharmacokinetics of Cabenuva have not been established in pediatric patients younger than 12 years of age or weighing less than 35 kg (ViiV, 2022).

Human Immunodeficiency Virus Type-1 (HIV-1)

An estimated 1.2 million people in the United States are living with the human immunodeficiency virus (HIV) (CDC, 2021a). The predominant and most common type of HIV virus is referred to as HIV-1. HIV-1 accounts for most of all HIV infections worldwide. HIV attacks the body’s immune system, specifically the CD4 cells (T cells), which help the immune system fight off infections. Untreated, HIV reduces the number of CD4 cells (T cells) in the body, making persons more prone to get other infections or infection-related cancers. When a CD4 count is lower than 200 cell/mm

, and/or opportunistic infections or cancers take advantage of an already weakened immune system, a person may receive a diagnosis of AIDS, acquired immunodeficiency syndrome, which is the last stage of HIV infection. There is no cure, but there are many medicines, known as antiretroviral therapy (ART), that fight HIV infection and lower the risk of developing AIDS (HIVinfo.nih.gov, 2020; CDC, 2020; Sax and Wood, 2019).

Viral load tests measure the number of copies of HIV RNA in a millilitre of blood. A low viral load means the virus is not very active and that the HIV treatment is working. A high viral load means the virus is more active and the HIV treatment is not working well. The higher the viral load, the more risk for opportunistic infections and/or diseases related to a weak immune system, as well as higher risk for developing AIDS. Viral suppression is defined as having less than 200 copies of HIV per milliliter of blood.The main goal of HIV drugs is to reduce the HIV viral load to an "undetectable" level, meaning that the HIV RNA is below the level that the test is able to count (CDC, 2021b; NLM, 2020).

There are many HIV medicines available to treat HIV-1. The HIV medicines [antiretroviral therapy (ART)] are grouped into seven drug classes according to how they fight HIV. These classes include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 antagonists, integrase strand transfer inhibitors (INSTIs), and post-attachment inhibitors. A person’s initial HIV regimen usually includes three HIV medicines from at least two different HIV drug classes (Clincialinfo.hiv.gov, 2021; HIVinfo.nih.gov, 2020).

On January 27, 2021, the U.S. FDA approved Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) long-acting complete regimen for the treatment of HIV-1 infection in adults. Cabenuva is indicated as a replacement to the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either oral dosing of cabotegravir or rilpivirine. This is the first FDA-approved injectable, complete regimen for HIV-1 infected adults that is administered intramuscularly once a month. FDA approval was based on the results of two phase 3, randomized, multicenter, active-controlled, parallel-arm, open-label, non-inferiority trials (FLAIR, [NCT02938520]), (n = 629); ATLAS, [NCT02951052]), (n = 616) (FDA, 2021).

The FLAIR trial evaluated the efficacy of long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. Adults (n=629) with HIV-1 infection who had not previously received antiretroviral therapy were given daily oral induction therapy with dolutegravir-abacavir-lamivudine for 20 weeks. Participants (n=566) who had an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were randomly assigned (1:1) to continue the current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly injections of long-acting cabotegravir plus rilpivirine. The primary end point was the percentage of participants who had an HIV-1 RNA level of 50 copies per milliliter or higher at week 48. At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 participants (2.1%) who received long-acting therapy and in 7 of 283 (2.5%) who received oral therapy (adjusted difference, -0.4 percentage points; 95% confidence interval [CI], -2.8 to 2.1), a result that met the criterion for noninferiority for the primary end point (margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% who received long-acting therapy and in 93.3% who received oral therapy (adjusted difference, 0.4 percentage points; 95% CI, -3.7 to 4.5), a result that met the criterion for noninferiority for this end point (margin, -10 percentage points). Of the participants who received long-acting therapy, 86% reported injection-site reactions (median duration, 3 days; mild or moderate severity, 99% of cases); 4 participants withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, who received long-acting therapy and in 4% and 1% who received oral therapy. Treatment satisfaction increased after participants switched to long-acting therapy; 91% preferred long-acting therapy at week 48. In conclusion, therapy with long-acting cabotegravir plus rilpivirine was noninferior to oral therapy with dolutegravir-abacavir-lamivudine with regard to maintaining HIV-1 suppression. Injection-site reactions were common (Orkin et al., 2020).

The ATLAS trial evaluated the efficacy of long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. Patients (n=616) who had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy were randomly assigned (1:1) to either continue their oral therapy or switch to monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and long-acting rilpivirine, a nonnucleoside reverse-transcriptase inhibitor. The primary end point was the percentage of participants with an HIV-1 RNA level of 50 copies per milliliter or higher at week 48. Treatment was initiated in 308 participants per group. At week 48, HIV-1 RNA levels of 50 copies per milliliter or higher were found in 5 participants (1.6%) receiving long-acting therapy and in 3 (1.0%) receiving oral therapy (adjusted difference, 0.6 percentage points; 95% confidence interval [CI], -1.2 to 2.5), a result that met the criterion for noninferiority for the primary end point (noninferiority margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 92.5% of participants receiving long-acting therapy and in 95.5% of those receiving oral therapy (adjusted difference, -3.0 percentage points; 95% CI, -6.7 to 0.7), a result that met the criterion for noninferiority for this end point (noninferiority margin, -10 percentage points). Virologic failure was confirmed in 3 participants who received long-acting therapy and 4 participants who received oral therapy. Adverse events were more common in the long-acting-therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy and was mild or moderate in most cases; 1% withdrew because of this event. Serious adverse events were reported in no more than 5% of participants in each group. In conclusion, monthly injections of long-acting cabotegravir and rilpivirine were noninferior to standard oral therapy for maintaining HIV-1 suppression. Injection-related adverse events were common but only infrequently led to medication withdrawal (Swindells et al., 2020).

In both studies, 7% had CD4+ cell count less than 350 cells/mm

. In ATLAS, subjects received an NNRTI (50%), integrase inhibitor (33%), or protease inhibitor (17%) as their baseline third-agent class prior to randomization; this was similar between treatment arms. Subjects with hepatitis B co-infection were excluded from the trial.

Criteria for Initial Approval

Aetna considers long-acting cabotegravir and rilpivirine injectable (Cabenuva) medically necessary for the treatment of human immunodeficiency virus type 1 (HIV-1) infection when

of the following criteria are met:

Aetna considers all other indications as experimental and investigational.

Continuation of Therapy

Aetna considers continuation of Cabenuva therapy medically necessary for treatment of human immunodeficiency virus type 1 (HIV-1) infection when the member has not experienced a virologic failure while on the requested drug, defined as two consecutive plasma HIV-1 RNA levels greater than or equal to 200 copies per mL.

Dosage and Administration

Cabenuva is a 2-drug co-packaged product of cabotegravir and rilpivirine. For intramuscular (IM) gluteal injection only. Cabenuva must be administered by a healthcare professional.

Cabenuva 400-mg/600-mg Kit:

Cabenuva 600-mg/900-mg Kit:

Human Immunodeficiency Virus type-1 (HIV-1)

The following Cabanuva dosing is indicated for adults and adolescents 12 years of age and older and weighing at least 35 kg.

Prior to initiating treatment with Cabenuva, oral lead-in dosing may be considered to assess the tolerability of cabotegravir and rilpivirine with

the recommended dosage used for approximately 1 month.

Recommended Monthly Dosing Schedule: Initiate injections of Cabenuva (600 mg of cabotegravir and 900 mg of rilpivirine) on the last day of current antiretroviral therapy or oral lead-in and continue with injections of Cabenuva (400 mg of cabotegravir and 600 mg of rilpivirine) every month thereafter.

Recommended Every-2-Month Dosing Schedule: Initiate injections of Cabenuva (600 mg of cabotegravir and 900 mg of rilpivirine) on the last day of current antiretroviral therapy or oral lead-in for 2 consecutive months and continue with injections of Cabanuva every 2 months thereafter.

Source: ViiV, 2022