Efficacy, Safety and Effectiveness of Injectable Cabotegravir/Rilpivirine in Improving HIV-1 Control in Sub-Saharan Africa: A Pragmatic Phase 3b Open-Label Randomized Controlled Trial

Background: At the end of December 2021, only 2 out of 3 people living with HIV (PLHIV) had achieved viral suppression which means there was control of the amount of HIV virus in their blood. Internationally, the goal is to have 95% of PLHIV being virally suppressed. The main driver to successful HIV treatment and control is taking medication as per the instructions of the healthcare providers. Simplifying treatment and overcoming the need for daily pill taking is an important step in making it easier to take medication correctly. This will also improve the quality of life and reduce the death and disability caused by HIV treatment failure. Monthly or 2-monthly injectable drugs offer a greatly reduced dosing frequency. This dosing plan may be a better option for patients who find it difficult to take medication as prescribed and it may result in reduced stigma and greater treatment satisfaction.

This research will build upon data provided by the ongoing Cabotegravir (CAB) and Rilpivirine (RPV) Efficacy and Safety (CARES) study in Uganda, Kenya, and South Africa that aims to determine whether the injectable HIV-1 drugs are as good as the current oral drugs in controlling the amount of HIV virus in PLHIV.

Objective: We would like to determine if changing to 2-monthly injections of the drugs CAB and RPV is as good as continuing on the current recommended daily oral antiretrovirals over a 12-month period in PLHIV who have in the past had difficulty in taking their medication as prescribed or had difficulty in engaging in care.

Participants and Methods: We will enroll 540 participants in 3 countries: Kenya, Uganda and South Africa. In Kenya, a total of 160 participants will be recruited from HIV clinics at Kenyatta National Hospital in Nairobi and Jaramogi Oginga Odinga Teaching and Referral Hospital in Kisumu, 80 at each site. After providing written informed consent, participants will be evaluated for eligibility for up to 3 months. Thereafter, half of them will have their HIV treatment changed to 2-monthly injectable treatment while the other half will remain on the treatment they have been using; this choice will be made randomly at the time each person is enrolled onto the study. Thereafter, each person will be followed up for 24 months. During this time, the amount of HIV virus in blood will be checked on months 2/3, 6, 8/9, 12, 18 and 24 alongside other laboratory and radiological tests assessing for safety. Procedures to minimize risk of COVID-19 infection amongst participants and staff will be implemented.

Background

At the end of December 2021, 68% of PLHIV globally had achieved virological suppression against the UNAIDS target of 95%. Virologic suppression is primarily dependent on adherence to antiretroviral therapy (ART). Simplifying treatment and overcoming the need for daily pill taking is an important step in increasing treatment compliance, improving quality of life and reducing the death and disability caused by HIV treatment failure. Long-acting (LA) injectable therapy offers a greatly reduced dosing frequency that may be a better option for patients with a history of sub-optimal adherence as it may result in reduced stigma, improved adherence and greater treatment satisfaction.

This study will build upon data provided by the ongoing Cabotegravir (CAB) and Rilpivirine (RPV) Efficacy and Safety (CARES) study in Uganda, Kenya, and South Africa that aims to determine whether the antiviral effect of switching to injectable cabotegravir and rilpivirine is non-inferior to continuation of first-line ART in virologically suppressed PLHIV.

Methods

This is a randomized, open-label multicenter, interventional study of 540 virologically suppressed (HIV-1 VL <200 c/mL) HIV-1 infected adults (18 years or older) who have a history of, or are at high risk of, sub-optimal adherence to daily oral ART and/or engagement in HIV care.

The study will take place in Kenya, Uganda and South Africa. In Kenya, 160 participants will be enrolled into the study, 80 each at Kenyatta National Hospital and Jaramogi Oginga Odinga Teaching and Referral Hospital. Participants will be randomized 1:1 to continue daily oral ART or switch to LA CAB / RPV, and will be followed for 24 months.

HIV-1 RNA viral load will be measured at months 2/3, 6, 8/9, 12 18 and 24. CD4 count, complete blood count, renal and liver function tests, glycated haemoglobin, fasting lipids, urinalysis and patient satisfaction will be measured at baseline and during follow up, along with other safety investigations. Procedures to minimize risk of COVID-19 infection amongst participants and staff will be implemented.

The primary efficacy endpoint of virologic response (HIV-1 RNA <50 copies/ml at 12 months) will be analysed for non-inferiority using the FDA snapshot method.

Conclusion

The results of this study will establish whether LA injectable therapy is an effective treatment option for PLHIV with a history of sub-optimal ART adherence or engagement in care.