A Phase IIIb, open-label, hybrid type III trial evaluating implementation strategies for long-acting cabotegravir plus long-acting rilpivirine every two months in HIV-1 infected, virologically suppressed adults in select European healthcare settings.

The treatment of HIV-1 infection has advanced since the first oral
antiretroviral agent (zidovudine, AZT) was approved for the treatment of HIV-1
infected individuals in 1987. Newer antiretrovirals are more potent, better
tolerated and have enabled the formulation of multiple regimens that can
provide viral suppression with a single tablet once daily. Moreover, clinic
visits for laboratory monitoring have become less frequent; current standard of
care for virally suppressed patients is a clinic visit with laboratory every
3-6 months. While there have been major advances in the field of HIV
therapeutics, tolerability, long term safety concerns and adherence remain
significant limitations to treatment success. Consistent lifetime daily
adherence is difficult for many patients, reducing effectiveness of these
treatments. Moreover, intermittent compliance can result in HIV drug
resistance, with subsequent regimens being more complicated to construct.

Long acting injectable versions of drugs are being developed to enable therapy
with infrequent dosing injection and represent an emerging paradigm for the
treatment of HIV infection. CAB is a potent integrase inhibitor that possesses
attributes that allow formulation and delivery as a long-acting product. RPV,
also formulated as a LA product, is a diarylpyrimidine derivative and a potent
non-nucleoside reverse transcriptase inhibitor (NNRTI) with in vitro activity
against wild type HIV-1 and select NNRTI-resistant mutants. A two-drug regimen
with CAB LA plus RPV LA (CAB LA + RPV LA) may offer many potential advantages
over daily oral regimens including infrequent dosing that decreases the daily
reminder to patients of their HIV status, decreased development of viral
resistance due to intermittent compliance with oral agents and overall
treatment satisfaction in virologically suppressed patients. Results to date
have demonstrated the efficacy of a two-drug regimen of CAB LA + RPV LA as
maintenance therapy with several on-going Phase 2 and 3 studies including
LATTE-2, ATLAS, FLAIR, and ATLAS 2M.

The overall objective of the CAB LA + RPV LA clinical development programme is
to develop a highly effective, well-tolerated, two-drug, long-acting injectable
regimen which has the potential to offer improved treatment convenience,
compliance and improved quality of life for people living with HIV compared to
current standard of care.

CAB LA + RPV LA represents a potential paradigm shift in the treatment of HIV
with respect to the transition from daily oral antiretroviral therapy (ART) to
long-acting injectable therapy. As such, it is important to understand how to
optimise the implementation of CAB LA + RPV LA from the perspective of the
patient as well as the healthcare provider, in order to mitigate any barriers
to implementation in routine care.
Information from this study will be used to understand what level of clinic
training and staff support is necessary for successful implementation of CAB LA
+ RPV LA. It will also be used to identify strategies to overcome any perceived
barriers for the patients receiving the drug, as well as the healthcare
providers and institutions administering the drug.

Patient:
For the patient this is a single-arm, open-label interventional study in
respect to the drug regimen whereby all patients enrolled will receive the same
intervention of the CAB LA + RPV LA regimen with a month oral lead in at Day 1
followed by CAB LA + RPV LA injections at Month 1, Month 2 and every 2 months
thereafter. .

For Clinics:
For the implementation science aspect, this is a two-arm study where clinics
will be randomized to either Enhanced or Standard Implementation Arms at the
country level

Arm 1: The Enhanced Implementation Arm (arm-e) contains the Skilled Wrap-Around
Team (SWAT) which is an interactive problem-solving meeting and an introduction
to the principles of Continuous Quality Improvement (CQI) with follow-up CQI
calls.

Arm 2: The Standard Implementation Arm (arm-s) will provide sites with the
traditional standard practices for each country at the time of product
availability provided by a medical science liaison or medical lead.

Both arms will have access to the toolkits aimed to support education and
proper administration of CAB LA + RPV LA.

Cabotegravir long-acting (CAB LA) and rilpivirine long-acting (RPV LA) is an
investigational HIV-1 treatment regimen administered as two individual
intramuscular injections, at the same time, once every two (2) months
(following an oral lead-in period and initiation period).

Subject:
Burden:
Fill out questionnaires: 4x
Physical Examination: 6x
Interview by external party (if selected): 2x

Risks study procedures:
Blood samples can be painful and bruising may occur
Injection site reaction - the IP is given via IM injection. This can cause;
pain or feeling uncomfortable, redness, swelling, itching, a bruise, lumps
(hard swelling under the skin) or irritation at the puncture site.

Risk:
CAB LA
In more than 10% of the subjects: headache, fever and a reaction at the place
where the injection was administered ('the puncture site')
In 1-10% of subjects: rashes, diarrhea or thin stools, nausea, vomiting,
flatulence, abdominal pain, insomnia, nightmares, dizziness, anxiety,
depressive feelings or thoughts, muscle pain, fatigue, feeling of weakness or
discomfort
In 0.1-1% of subjects: drowsiness, dizziness or fainting during or after an
injection, liver problems, transaminase increase (a protein in your blood),
increase in weight
Allergic reactions to integrase inhibitors such as CAB have been reported.
Symptoms included 'feeling sick', rash, fever, fatigue, swelling (sometimes of
face or mouth with breathing problems), blisters, mouth ulcers, painful
inflamed eyes, joint pain and muscle pain
Abnormal liver values
Seizures and convulsions (seizures)

RPV (LA)
In 1-10% of subjects: decreased appetite, sleep disorders, nausea, discomfort
in the abdomen, dry mouth
In 0.1-1% of subjects: IRIS. IRIS is a condition in which some patients,
especially those who have been HIV positive for a long time, can get
inflammatory reactions. The symptoms are usually not specific. Symptoms include
fever and worsening of the underlying disease. These inflammatory reactions are
probably caused by the body's better resistance to inflammation. This is
because the treatment reduces the amount of virus in the body.
Rashes.
Increased liver values.

Resistance to one or more drugs against HIV
Some patients with HIV infection have occasional depressive feelings or
struggle with thoughts of self-harm or suicide

Site staff
Burden:
Fill out questionnaires: 3x
Interview by external party (about 4 people): 3x