Cabotegravir (Vocabria) & rilpivirine (Rekambys) injections

Vocabria and Rekambys are injectable antiretroviral products approved for use in combination. Each is a long-acting formulation of an antiretroviral drug, administered together every month or every two months.

Vocabria is the injectable form of the integrase inhibitor cabotegravir. Vocabria is marketed by ViiV Healthcare.

Rekambys is the injectable form of the non-nucleoside reverse transcriptase inhibitor rilpivirine. Rekambys is marketed by Janssen.

Vocabria and Rekambys were approved in the European Union and United Kingdom in 2020 for use in combination to treat HIV in people with fully suppressed viral load (< 50 copies/ml).

The two injectable agents were approved in Canada in 2020 and the United States in 2021 as a combined product with the name Cabenuva to treat HIV in people with fully suppressed viral load (< 50 copies/ml).

Effectiveness

The cabotegravir and rilpivirine injectable regimen was approved based on the results of three clinical trials.

The ATLAS study compared injectable cabotegravir and rilpivirine to oral antiretroviral treatment in 616 people with suppressed viral load for at least six months prior to study entry. Participants randomised to injectable treatment took cabotegravir and rilpivirine pills for a month before switching to injections. 92.5% of participants receiving long-acting therapy and 95.5% of those receiving oral therapy had a viral load below 50 copies/ml at week 48, a non-significant difference. (Swindells)

The FLAIR study compared injectable cabotegravir and rilpivirine to dolutegravir, abacavir and lamivudine (Triumeq) in 566 previously untreated people. All study participants received 20 weeks of induction treatment with dolutegravir, abacavir and lamivudine. At week 16, people with viral load below 50 copies/ml were randomised to continue the induction regimen or switch at week 20 to a one-month induction regimen of cabotegravir and rilpivirine tablets followed by monthly injections of cabotegravir and rilpivirine. At week 48, 93.6% of those who received long-acting therapy and 93.3% who received oral therapy had a viral load below 50 copies/ml. Treatment satisfaction increased after participants switched to long-acting therapy; 91% preferred long-acting therapy at week 48. (Orkin)

The ATLAS-2M study compared monthly or two-monthly injections of cabotegravir and rilpivirine in 1045 treatment-experienced adults with suppressed viral load. Thirty-seven per cent of participants had previously received the four-week injectable regimen in the ATLAS trial. At week 48, 94.3% of participants taking the two-monthly regimen and 93.5% of those taking the monthly regimen continued to have undetectable viral load (less than 50 copies/ml), showing that the two-monthly schedule was non-inferior to monthly administration.

Rates of virological failure (HIV RNA over 50 copies/ml) were 1.7% in the two-monthly group versus 1.0% in the monthly treatment group. Eight people (1.5%) on the two-monthly regimen and two people (0.4%) on the monthly regimen experienced confirmed virological failure, defined as two consecutive viral loads above 200 copies/ml. Nine of the ten people with confirmed virological failure regained viral suppression when switched to a fully active oral regimen. However, those using the two-monthly regimen were more likely to have drug resistance mutations. (Overton)

The two-monthly regimen has not been directly compared to oral antiretroviral therapies.

Taking it

People starting the injectable long-acting regimen will switch from their existing antiretroviral treatment to take cabotegravir and rilpivirine tablets once daily for a month before beginning injectable treatment. Lead-in treatment is designed to assess tolerability and allows discontinuation before long-acting treatment begins.

Injectable treatment can be given monthly or two-monthly. Depending on whether the injection is every one or two months, different doses are injected.

Cabotegravir and rilpivirine are administered as two intramuscular injections in the buttocks at the same appointment.

If scheduled injections are missed by more than one week, oral treatment with cabotegravir and rilpivirine tablets should be resumed.

Antacids containing magnesium or calcium should be taken at least two hours before or four hours after cabotegravir tablets.

Side effects

A combined analysis of the FLAIR and ATLAS study populations found that 83% of injectable recipients experienced injection site reactions. Injection site reactions were more frequent during the first months of treatment and resolved within seven days in most participants (88%). Up to 1% of trial participants discontinued injectable treatment because of injection site reactions. (Rizzardini)

In ATLAS-2M, 76% of participants experienced injection site reactions. (Overton)

Other common side effects were raised temperature, muscle pain, tiredness, weakness, depression, dizziness, abnormal dreams, diarrhoea, nausea, vomiting, abdominal pain and rash.

Lowered white and red blood cell count, raised total and LDL cholesterol, raised triglycerides and raised pancreatic amylase were common in clinical trial participants.

Rare cases of transient post-injection reactions after the rilpivirine injection were reported in clinical trials. Features included shortness of breath, agitation, abdominal cramping, flushing, sweating, oral numbness and changes in blood pressure.

Hypersensitivity reactions have been reported with other integrase inhibitors in a small number of people. These reactions have not been reported to date with cabotegravir use.

Weight gain has been reported after starting antiretroviral treatment and analysis of clinical studies shows that weight gain is greater in people starting integrase inhibitor-based treatment. Clinical trials of the injectable regimen show modest increases in weight. In the FLAIR study, which compared injectable treatment containing an integrase inhibitor to another integrase inhibitor-based regimen in previously untreated people, there was no significant difference in weight gain (+1.3kg vs +1.5kg) over 48 weeks. In the ATLAS study, which compared injectable treatment to oral treatment in treatment-experienced people, weight gain was greater in the injectable group (+1.8kg vs +0.3kg). One-third of participants in the ATLAS study were taking an integrase inhibitor at baseline. In the ATLAS-2M study in treatment-experienced patients continuing or switching to the injectable regimen, weight gain was modest (+1kg at week 48). (Orkin; Swindells; Overton)

Drug interactions

The following medicines should not be used at the same time as cabotegravir and rilpivirine injectable treatment:

• the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• the antimycobacterials rifabutin, rifampicin, rifapentine
• the systemic glucocorticoid dexamethasone, except as a single-dose treatment
• St John’s wort (Hypericum perforatum).

Resistance

Low concentrations of cabotegravir may remain in the bloodstream for up to 12 months or more after the last injection but these are not enough to maintain suppression of HIV. Low concentrations of rilpivirine may persist for up to four years.

Viral resistance may develop if a new antiretroviral regimen is not started one month after stopping monthly dosing of the injectable regimen or within two months after stopping two-monthly dosing of the injectable regimen.

Analysis of the FLAIR and ATLAS studies shows that a combination of at least two of the following baseline factors may be associated with an increased risk of virological failure: archived rilpivirine resistance mutations, HIV-1 subtype A6/A1, or BMI ≥ 30 kg/m².Where treatment history is uncertain and previous resistance testing data is unavailable, caution is warranted in the presence of either BMI ≥30 kg/m² or HIV-1 A6/A1 subtype.

Pregnancy

Cabotegravir and rilpivirine long-acting treatment is not recommended during pregnancy due to lack of data. Rilpivirine levels may be reduced during pregnancy, increasing the risk of virological failure.

Children

Cabotegravir and rilpivirine long-acting treatment is not approved for use in children.

Further information

See rilpivirine for further information.