- Healthcare teams from diverse European HIV clinics reported that the implementation of the complete long-acting regimen was acceptable, appropriate, and feasible, with the majority of practices achieving optimal implementation within one to three months
- 81% of people living with HIV who participated in the study reported that the complete long-acting regimen was less stigmatising than daily oral treatment
LONDON–(BUSINESS WIRE)–ViiV Healthcare, the global specialist HIV company majority-owned by GSK, with Pfizer and Shionogi as shareholders, today presented findings from the CARISEL study (Cabotegravir And Rilpivirine Implementation Study in European Locations). The study, which evaluated the perspectives of people living with HIV and healthcare teams through surveys and interviews in addition to evaluating clinical effectiveness, demonstrated that ViiV Healthcare’s Vocabria (cabotegravir injection) and Janssen Pharmaceutical Companies of Johnson and Johnson’s Rekambys (rilpivirine long-acting injectable suspension) was successfully implemented across a range of European healthcare settings.1 The 12-month findings from the implementation study of the first and only complete long-acting regimen for HIV treatment were presented today at the 30th HIV Glasgow Conference being held in Glasgow, Scotland and virtually, from 23 – 26 October.
At 12 months, primary findings from the CARISEL study demonstrated that despite most European clinics having no prior long-acting cabotegravir and rilpivirine experience, there was high acceptability, appropriateness, and feasibility among clinic staff towards its implementation (mean scores ≥ 3.8 on a 5-point Likert scale) as well as the long-acting regimen itself (mean scores ≥ 4.2). Of 70 staff participants in the study, 56% reported optimal implementation within one to three months, with 68% of staff participants believing the time spent in clinic was “very” or “extremely acceptable”. 1
Across the duration of the CARISEL study, people living with HIV also found that long-acting cabotegravir and rilpivirine was highly acceptable, appropriate, and feasible to implement (mean scores ≥ 4.47 on a 5-point Likert scale).1 Long-acting cabotegravir and rilpivirine demonstrated high clinical effectiveness and a low rate of viral failure throughout the duration of the trial.
At Month 12, 373 of 437 (87%) of people living with HIV in the trial maintained viral suppression (HIV-1 RNA <50 copies/mL), and the proportion of participants with HIV-1 RNA ≥50 copies/mL was 0.7% (FDA Snapshot).1
Berend J. van Welzen, M.D., CARISEL Investigator, UMC Utrecht, The Netherlands said: “The findings of the CARISEL study show that long-acting cabotegravir and rilpivirine was not only a highly effective treatment option for people living with HIV with a low rate of viral failure, but that the regimen was also highly acceptable, appropriate, and feasible to implement across a range of European countries and clinics. As healthcare providers and clinics look for real world evidence on the successful implementation of this innovative treatment, the findings of CARISEL provide continued and strong evidence for its applicability across diverse healthcare settings.”
Perspectives from healthcare providers and clinical staff from the CARISEL study2
During the CARISEL study, quantitative and qualitative perceptions about the implementation of long-acting cabotegravir and rilpivirine were collected from staff study participants at 18 participating clinics at Month 1 (70 respondents), Month 5 (68 respondents), and Month 12 (62 respondents). At Month 12, quantitative data showed most study staff participants (76%) felt “very” or “extremely positive” about implementing long-acting cabotegravir and rilpivirine, with staff participants believing that the regimen was appropriate for a wide variety of patients including, but not limited to, those who are tired of daily pills, those concerned with disclosure of HIV status, and those who had experienced stress regarding daily pill compliance.
Staff participants were surveyed on their top reported barriers to the implementation of long-acting cabotegravir and rilpivirine following the first month of the CARISEL study. At the conclusion of the study, all top five perceived barriers by staff study participants that were initially reported at Month 1 had markedly decreased by Month 12, including risk of resistance for non-adherent patients (M1 35%, M12 16%), having enough injection administrators on a daily basis (M1 35%, M12 24%), patient injection-related pain/soreness (M1 33%, M12 16%), scheduling around patient holidays (M1 32%, M12 8%), and patients being non-virologically suppressed due to missed dose (M1 30%, M12 15%).
At the conclusion of the study, staff study participants identified several tips for optimising implementation success, including:
- Using techniques to minimise injection discomfort, including slowing the speed of the injection (60%), ensuring that the medication had reached room temperature (57%), and having the patient relax their muscle prior to injection (53%)
- Education about treatment, including information on pain/soreness to discuss with patients before injections, and additional information about medication preparation and injections
Perspectives from people living with HIV from the CARISEL study3
During the study, 437 virologically suppressed adults living with HIV were enrolled at 18 participating clinical sites, with 379 participants receiving long-acting cabotegravir and rilpivirine and completing questionnaires on the regimen’s acceptability, appropriateness, and feasibility through Month 12. People living with HIV also answered questions about facilitators and barriers to treatment, including stigma, pain/discomfort, and treatment preference.
Detailed findings from people living with HIV who participated in the study showed that at Month 12:
- 99% preferred long-acting cabotegravir and rilpivirine compared to daily oral therapy
- 81% agreed that long-acting cabotegravir and rilpivirine was less stigmatising than oral medication
- 78% found the time spent in clinic for their injection visits to be very or extremely acceptable
- 85% found attending appointments every two months to be very or extremely acceptable
- 95% of participants would recommend long-acting cabotegravir and rilpivirine to other people living with HIV
Although 56% of patients noted that injection pain or soreness was the most difficult part of treatment, the mean pain score during the most recent injection at Month 12 was 3 on a 0 (“no pain”) to 10 (“extreme pain”) scale.
Harmony P. Garges, M.D., MPH, Chief Medical Officer at ViiV Healthcare said: “The need for long-acting cabotegravir and rilpivirine is clear, with 81% of people living with HIV in the study agreeing that the every-two-month regimen was less stigmatising than oral medication and 99% preferring it to daily oral therapy. In addition to developing paradigm-shifting treatment regimens, it’s essential that we also study how these medicines are used and implemented in the real world through studies like CARISEL to ensure that all are able to benefit from this innovation. The widespread acceptability and feasibility of this complete long-acting regimen across European countries and healthcare practices reinforces its potential to help address the evolving needs of people living with HIV.”
ViiV Healthcare’s cabotegravir in combination with Janssen Pharmaceutical Companies of Johnson & Johnson’s rilpivirine was co-developed as part of a collaboration with Janssen and builds on ViiV Healthcare’s industry-leading portfolio that is centred on delivering innovative medicines for the HIV community. Additional findings and analyses from the CARISEL study, which include the potential administration of Vocabria and Rekambys outside of the clinic environment, will be presented at future congresses.
About CARISEL (NCT04399551)
CARISEL is a Phase IIIb, one-year, multicentre implementation-effectiveness trial (open-label single arm switch study for patient study participants), examining different implementation strategies for long-acting cabotegravir and rilpivirine in a broad range of clinical settings across European countries to identify strategies which best meet the needs in each local context. The study, which involved 437 patient study participants and 70 healthcare team participants from 18 clinics across Spain, France, Netherlands, Belgium, and Germany, assessed the effect of various implementation strategies on the acceptability, appropriateness, and feasibility of delivering the new long-acting regimen of cabotegravir and rilpivirine to appropriate people living with HIV.
About Vocabria (cabotegravir injection) and Rekambys (rilpivirine injection)
Cabotegravir injection used in combination with rilpivirine injection is a complete long-acting regimen dosed monthly or every 2-months, for the treatment of HIV-1 in adults who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the NNRTI and INI class. Cabotegravir and rilpivirine injections are administered as two intramuscular (IM) injections in the buttocks by a healthcare professional at the same appointment.
The complete regimen combines the integrase strand transfer inhibitor (INSTI) cabotegravir, developed by ViiV Healthcare, with rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) developed by Janssen Sciences Ireland UC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson.
INSTIs, like cabotegravir, inhibit HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection. Rilpivirine is an NNRTI that works by interfering with an enzyme called reverse transcriptase, which in turn stops the virus from multiplying.
Trademarks are owned by or licensed to the ViiV Healthcare group of companies.
Important Safety Information
The following Important Safety Information is based on the Summary of Product Characteristics for Vocabria. Please consult the full Summary of Product Characteristics for all the safety information.
Vocabria (cabotegravir) injection is indicated, in combination with rilpivirine injection, for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the NNRTI and INI class
Vocabria injection is indicated for the treatment of HIV-1 in combination with rilpivirine injection, therefore, the prescribing information for rilpivirine injection should be consulted for recommended dosing.
Vocabria tablets are indicated in combination with rilpivirine tablets for the short-term treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the NNRTI and INI class for:
- oral lead in to assess tolerability of Vocabria and rilpivirine prior to administration of long acting Vocabria injection plus long acting rilpivirine injection.
- oral therapy for adults who will miss planned dosing with Vocabria injection plus rilpivirine injection.
Vocabria tablets are only indicated for treatment of HIV-1 in combination with rilpivirine tablets, therefore, the prescribing information for Edurant tablets should also be consulted for recommended dosing.
Prior to starting Vocabria injection, healthcare professionals should have carefully selected patients who agree to the required injection schedule and counsel patients about the importance of adherence to scheduled dosing visits to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance with missed doses.
Following discontinuation of Vocabria and rilpivirine injection, it is essential to adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the final injection of Vocabria when dosed monthly and no later than two months after the final injection of Vocabria when dosed every 2 months.
Elderly (≥65 years of age): No dose adjustment is required in elderly patients. There are limited data available on the use of cabotegravir in patients aged 65 years and over.
Paediatrics (<18 years of age): The safety and efficacy of Vocabria in children and adolescents aged under 18 years have not been established. No data are available.
Contraindications
Hypersensitivity to cabotegravir or rilpivirine or to any of the excipients.
Concomitant use with: rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenytoin or phenobarbital
Special Warnings and Precautions for Use
Vocabria injection
Risk of resistance following treatment discontinuation
To minimise the risk of developing viral resistance it is essential to adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the final injection of Vocabria when dosed monthly and no later than two months after the final injection of Vocabria when dosed every 2 months.
Residual concentrations of cabotegravir may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer), therefore, physicians should take the prolonged release characteristics of Vocabria injection into consideration when the medicinal product is discontinued.
If virologic failure is suspected, an alternative regimen should be adopted as soon as possible.
Baseline factors associated with virological failure
Before starting the regimen, it should be taken into account that multivariable analyses indicate that a combination of at least 2 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. In patients with an incomplete or uncertain treatment history without pre-treatment resistance analyses, caution is warranted in the presence of either BMI ≥30 kg/m2 or HIV-1 A6/A1 subtype.
Hypersensitivity reactions
Hypersensitivity reactions have been reported in association with other integrase inhibitors. These reactions were characterised by rash, constitutional findings and sometimes organ dysfunction, including liver injury. While no such reactions have been observed to date in association with Vocabria, physicians should remain vigilant and should discontinue Vocabria and other suspected medicinal products immediately, should signs or symptoms of hypersensitivity develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia or angioedema). Clinical status, including liver aminotransferases should be monitored and appropriate therapy initiated. Administration of oral lead-in is recommended to help identify patients who may be at risk of a hypersensitivity reaction.
Hepatotoxicity
Hepatotoxicity has been reported in a limited number of patients receiving Vocabria with or without known pre-existing hepatic disease.
Monitoring of liver chemistries is recommended and treatment with Vocabria should be discontinued if hepatotoxicity is suspected.
HBV/HCV co-infection
Patients with hepatitis B co-infection were excluded from studies with Vocabria. It is not recommended to initiate Vocabria in patients with hepatitis B co-infection. Physicians should refer to current treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus.
Limited data is available in patients with hepatitis C co-infection. Monitoring of liver function is recommended in patients with hepatitis C co-infection.
Interactions with medicinal products
Caution should be given to prescribing Vocabria injection and tablets with medicinal products that may reduce its exposure.
Concomitant use of Vocabria injection with rifabutin is not recommended.
Polyvalent cation containing antacids are recommended to be taken at least 2 hours before and 4 hours after taking Vocabria tablets.
Effect of other medicinal products on the pharmacokinetics of cabotegravir
Cabotegravir is primarily metabolised by uridine diphosphate glucuronosyl transferase (UGT) 1A1 and to a lesser extent by UGT1A9. Medicinal products which are strong inducers of UGT1A1 or UGT1A9 are expected to decrease cabotegravir plasma concentrations leading to lack of efficacy.
Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions (ARs) from monthly dosing studies were injection site reactions (up to 84%), headache (up to 12%) and pyrexia* (10%).
The most frequently reported ARs from ATLAS-2M every 2-month dosing were injection site reactions (76%), headache (7%) and pyrexia* (7%).
*Pyrexia includes the following: feeling hot, body temperature increased.
Description of selected adverse reactions
Local injection site reactions (ISRs)
Up to 1% of subjects discontinued treatment with Vocabria plus rilpivirine because of ISRs. When dosing monthly, up to 84% of subjects reported injection site reactions; out of 30393 injections, 6815 ISRs were reported. When dosing every 2 months, 76% of patients reported injection site reactions; out of 8470 injections, 2507 ISRs were reported.
The severity of reactions was generally mild (Grade 1, 70%-75% of subjects) or moderate (Grade 2, 27%-36% of subjects). 3-4% of subjects experienced severe (Grade 3) ISRs. The median duration of overall ISR events was 3 days. The percentage of subjects reporting ISRs decreased over time.
Weight increased
At the Week 48 time point, subjects in studies FLAIR and ATLAS, who received Vocabria plus rilpivirine gained a median of 1.5 kg in weight subjects continuing on their current antiretroviral therapy (CAR) gained a median of 1.0 kg (pooled analysis). In the individual studies FLAIR and ATLAS, the median weight gains in the Vocabria plus rilpivirine arms were 1.3 kg and 1.8 kg respectively, compared to 1.5 kg and 0.3 kg in the CAR arms.
At the 48 week time point, in ATLAS-2M the median weight gain in both the monthly and 2-monthly CAB+RPV dosing arms was 1.0 kg.
Pregnancy
There are a limited amount of data from the use of cabotegravir in pregnant women. The effect of Vocabria on human pregnancy is unknown.
Cabotegravir was not teratogenic when studied in pregnant rats and rabbits but, exposures higher than the therapeutic dose showed reproductive toxicity in animals. The relevance to human pregnancy is unknown.
Vocabria injection is not recommended during pregnancy unless the expected benefit justifies the potential risk to the foetus.
Cabotegravir has been detected in systemic circulation for up to 12 months or longer after an injection
Breast-feeding
It is expected that cabotegravir will be secreted into human milk based on animal data, although this has not been confirmed in humans. Cabotegravir may be present in human milk for up to 12 months or longer after the last cabotegravir injection.
It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
Rekambys (rilpivirine injection) ISI
The following Important Safety Information is based on the Summary of Product Characteristics for REKAMBYS (rilpivirine injection). Please consult the full Summary of Product Characteristics for all the safety information.
REKAMBYS is indicated, in combination with cabotegravir injection, for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection in adults who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with, agents of the NNRTI and INI class
REKAMBYS should always be co-administered with a cabotegravir injection. The prescribing information for cabotegravir injection should be consulted for recommended dosing.
REKAMBYS may be initiated with oral lead-in or without (direct to injection).
The healthcare professional and patient may decide to use rilpivirine tablets as an oral lead-in prior to the initiation of REKAMBYS injections to assess tolerability or proceed directly to REKAMBYS therapy.
Oral lead-in
When used for oral lead-in prior to the initiation of REKAMBYS, rilpivirine oral tablets, together with cabotegravir oral tablets, should be taken for approximately 1 month (at least 28 days) to assess tolerability to rilpivirine and cabotegravir. One rilpivirine 25mg tablet should be taken with a meal with one cabotegravir 30mg tablet once daily.
Prior to the initiation of REKAMBYS, rilpivirine oral tablets, together with cabotegravir oral tablets, should be taken for approximately 1 month (at least 28 days) to assess tolerability to rilpivirine and cabotegravir. One rilpivirine 25‑mg tablet should be taken with a meal with one cabotegravir 30‑mg tablet once daily.
Prior to starting REKAMBYS, the healthcare professional should carefully select patients who agree to the required injection schedule and counsel patients about the importance of adherence to scheduled dosing visits to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance associated with missed doses.
Following discontinuation of REKAMBYS in combination with cabotegravir injection, it is essential to adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the last every 1 month injection of REKAMBYS or two months after the last every 2 months injection of REKAMBYS.
Elderly: There is limited information regarding the use of REKAMBYS in patients > 65 years of age. No dose adjustment of REKAMBYS is required in older patients.
Paediatric Patients: The safety and efficacy of REKAMBYS in children and adolescents aged < 18 years have not been established. No data are available.
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
REKAMBYS must not be co‑administered with the following medicinal products, which may result in loss of therapeutic effect of REKAMBYS:
- 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).
Special Warnings and Precautions for Use
Risk of resistance following treatment discontinuation
To minimise the risk of developing viral resistance it is essential to adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the last every 1 month injection of REKAMBYS or two months after the last every 2 months injection of REKAMBYS.
If virologic failure is suspected, an alternative regimen should be adopted as soon as possible.
Long-acting properties of rilpivirine injection
Residual concentrations of rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 4 years in some patients) and should be considered upon discontinuation of REKAMBYS.
Contacts
ViiV Healthcare enquiries:
Media enquiries:
Catherine Harley
+44 7909 002 403 (London)
Rachel Jaikaran
+44 7823 532 755 (London)
GSK enquiries:
Media enquiries:
Tim Foley
+44 (0) 20 8047 5502 (London)
Simon Moore
+44 (0) 20 8047 5502 (London)
Kathleen Quinn
+1 202 603 5003 (Washington DC)
Lyndsay Meyer
+1 202 302 4595 (Washington DC)
Analyst/Investor enquiries:
Nick Stone
+44 (0) 7717 618834 (London)
James Dodwell
+44 (0) 20 8047 2406 (London)
Mick Readey
+44 (0) 7990 339653 (London)
Josh Williams
+44 (0) 7385 415719 (London)
Frannie DeFranco
+1 215 751 4855 (Philadelphia)