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Injectable Cabotegravir Evidence Gap Tracker

The Biomedical Prevention Implementation Collaborative (BioPIC) consists of more than 100 HIV prevention experts from 80 organisations and 20 countries and supports successful introduction of biomedical HIV prevention options, including injectable cabotegravir (CAB) for PrEP. BioPIC coordinates regular Think Tanks to identify priority CAB for PrEP evidence gaps and review evidence from implementation and modelling studies to track progress against addressing them.

Below is a summary of the latest insights on CAB for PrEP coming out of these studies, links to learn more, and information on where evidence is still needed, mapped against priority evidence gaps.

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    HIV Testing and Drug Resistance

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    In multiple HPTN 083/084 study participants, HIV acquisition during the pharmacokinetic tail did not result in INSTI resistance    		 LEARN MORE
    Landovitz Raphael J., Donnell Deborah, Clement Meredith E., Hanscom Brett, Cottle Leslie, Coelho Lara, et al. Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women. New England Journal of Medicine. 2021 Aug 11;385(7):595–608    		 REMAINING GAPS TO BE ADDRESSED
    Additional data on HIV acquisition, including during the pharmacokinetic tail, as the initial number CAB for PrEP users who acquired HIV in the study was small
    Delany-Moretlwe S, Hughes JP, Bock P, Ouma SG, Hunidzarira P, Kalonji D, et al. Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial. The Lancet. 2022 May 7;399(10337):1779–89 How to detect INSTI resistance in users who seroconvert during the pharmacokinetic tail phase
    Viral escape at high CAB levels can lead to INSTI resistance, and if HIV is not detected quickly after a CAB for PrEP failure, INSTI resistance can develop Optimal strategies to manage and treat current and former CAB users who have seroconverted; currently being investigated in the PICASSO study
    Though modelling has shown that the rollout of CAB for PrEP could lead to an overall increase in INSTI resistance, it is also likely to lead to an overall decrease in HIV incidence and deaths What can modelling tell us about the scale-up of CAB for PrEP? Impact of CAB for PrEP on INSTI resistance in real-world settings

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    Rapid diagnostic tests (RDTs) are sufficient for use with CAB for PrEP initiation and continuation and in line with a public health approach to testing, and there are no known advantages to using fourth generation RDTs over third generation RDTs; RNA testing may not be feasible in many settings due to cost, lengthy turnaround times, and lack of regulatory approvals    		 LEARN MORE
    Notes from: Coordinating Implementation Science for CAB for PrEP: HIV Testing, June 2024    		 REMAINING GAPS TO BE ADDRESSED
    Whether HIV self-testing can be used for CAB for PrEP initiation and continuation (currently under review by WHO)
    CAB for PrEP will never be as cost effective as oral PrEP if RNA testing is required, and modelling suggests a limited impact of RNA testing on INSTI resistance related to use of CAB for PrEP What can modelling tell us about the scale-up of CAB for PrEP? How to manage costs of CAB for PrEP rollout in settings where RNA testing is required
    In the HPTN 083 Open Label Extension, RNA testing performed poorly for detecting HIV infection during CAB for PrEP injections, with performance better immediately prior to CAB for PrEP initiation; most isolated positive RNA test results while on CAB for PrEP were false positive results Landovitz R. Performance characteristics of HIV RNA screening with long-acting injectable cabotegravir (CAB-LA) pre-exposure prophylaxis (PrEP) in the multicenter global HIV Prevention Trials Network 083 (HPTN 083) Study. In Munich, Germany; 2024 How to manage false positives in contexts where RNA testing is required for CAB for PrEP continuation
    If an early HIV infection is not diagnosed before CAB for PrEP is started, CAB can make it challenging to diagnose later on Eshleman SH. The LEVI Syndrome: Characteristics of early HIV infection with Cabotegravir for PrEP. In Seattle, WA, USA; 2023 How to resolve discrepant results and diagnose HIV, particularly where there is a discrepancy between RNA testing and rapid testing-this is being evaluated in the HPTN 083/084 Open Label Extension (OLE) and tracked across implementation studies and early programmatic rollout
    Rapid tests can result in false negatives if administered too soon after HIV transmission HIV Testing Overview • The number of positive cases rapid testing for CAB for PrEP initiation and continuation is likely to miss-this is being evaluated under the CATALYST study

    • Optimal strategies for providers to manage CAB for PrEP users they strongly suspect have acute HIV
    Rapid tests can result in false positives due to frequency of testing and factors like co-infections, pregnancy, and steroid use Optimal strategies for providers to manage false positives

    Patterns of Use

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    Several models have found that introduction of CAB for PrEP would reduce HIV incidence, with the % reduction dependent on context, such as location, population, and uptake vs oral PrEP    		 LEARN MORE
    What can modelling tell us about the scale-up of CAB for PrEP?    		 REMAINING GAPS TO BE ADDRESSED
    Impact of CAB for PrEP on HIV incidence in real-world settings
    Modelling has shown CAB for PrEP could have a larger impact than oral PrEP with the same coverage, and that the impact is larger if rolled out to both men and women vs women only Notes from: Linking Modellers with the Latest CAB for PrEP Implementation Science Evidence, March 2024 Impact of CAB for PrEP vs oral PrEP rollout in real-world settings

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    In CAB/Rilpivirine (RPV) for treatment, direct to injection CAB has shown similar safety and efficacy profiles as that with an oral lead-in, though it is associated with lower CAB concentrations in users with high body mass index    		 REMAINING GAPS TO BE ADDRESSED
    Additional pharmacokinetics data on initiation of CAB for PrEP without an oral lead-in to understand generalisability of CAB/RPV for treatment findings—this is being evaluated in the HPTN 083/084 OLE
    In the countries that have begun the HPTN 083 OLE, 36% of participants have chosen the oral lead-in, while in HPTN 084 OLE, 15% have chosen the oral lead-in Reasons for choosing the oral lead-in vs direct to injection

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    No evidence to date    		 REMAINING GAPS TO BE ADDRESSED
    Impact of a CAB for PrEP user bridging with oral PrEP

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    96% of participants in the HPTN 083 OLE in the USA chose CAB for PrEP- though this is not necessarily generalisable as participants had joined the trial because they were interested in CAB; there is no specific subgroup driving this choice disparity; 70% who chose CAB cited a preference for injections to pills generally, with only 15% citing efficacy as the reason for their choice    		 LEARN MORE
    Slides from: Bridging from the HPTN 083 and 084 Open Label Extensions to Implementation, March 2023    		 REMAINING GAPS TO BE ADDRESSED
    User preference outside the context of a CAB trial, and outside the USA
    • 78% of participants in the HPTN 084 OLE chose CAB for PrEP; those who chose oral PrEP noted fear of injection site pain, while those who chose CAB noted preference for a more discreet, convenient method; partners, family, and others were influential in decision making

    • There were different patterns of choice of CAB vs oral PrEP at site level in HPTN 084, which could suggest multiple factors, including the influence of providers, users’ social networks, and their community, impacting choice; while this was not observed in HPTN 083, there were differences in choice of oral lead-in vs direct to injection at site level which may also have been provider or community influence

    		 Slides from: Bridging from the HPTN 083 and 084 Open Label Extensions to Implementation, March 2023 Reasons for method preference in real world contexts, including influence of providers and community in user choice
    In the SEARCH study, participants in the study arm were offered a choice between oral PrEP, PEP, and CAB for PrEP and the option to switch during the study, vs a choice between oral PrEP and PEP in the standard of care (SoC) arm; PrEP coverage in the study arm was 70% vs 13% in the SoC arm, with 56% in the study arm selecting CAB for PrEP; 42% of those who chose CAB for PrEP were not on any prevention product in the prior month; 28% of participants used two different products during the study; the study arm ended with zero incidence of HIV vs 1.8% in the SoC arm Webinar: Discussing Early Results from the SEARCH Dynamic Choice Study How to effectively offer choice at scale

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    A subset of the PrEP Choice Investigators group is looking into harmonising indicators around patterns of use; a proposed new indicator includes Person Years of PrEP dispensed (PYP), which uses the volume and type of PrEP prescribed and number of PrEP visits to estimate PrEP coverage; early evidence shows this information is feasible to collect from facility records    		 LEARN MORE
    Webinar: You Get What You Measure: Why Monitoring for PrEP Choice Helps Tell Our Story     		REMAINING GAPS TO BE ADDRESSED
    Meaningful indicators on patterns of use; feasibility of collecting data for PYP at scale

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    Early data suggests some dose forgiveness in three month dosing in individuals assigned female at birth (AFAB), but not those assigned male at birth; however, some AFAB trial participants were found to have lower CAB concentrations at three months which may suggest lower efficacy so three month dosing is not recommended    		 LEARN MORE
    Slides from: Bridging from the HPTN 083 and 084 Open Label Extensions to Implementation, March 2023    		 REMAINING GAPS TO BE ADDRESSED
    Data do not support three month dosing, and further research is not recommended with this formulation of CAB; more data is required on population and individual differences in the pharmacokinetics of CAB and its predictors, including why some individuals assigned male at birth got infected despite on-time injections

    Safety, Acceptability, and Efficacy for Diverse Populations

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    CAB for PrEP is safe and well tolerated in pregnancy; while initial evidence suggests that CAB concentrations decrease throughout pregnancy, they remain above exposure targets, so dose modifications are unlikely to be required    		 LEARN MORE
    Delany-Moretlwe S. Initial evaluation of injectable cabotegravir (CAB-LA) safety during pregnancy in the HPTN 084 open-label extension. In Munich, Germany 2024

    Marzinke M. Evaluation of long-acting cabotegravir (CAB-LA) pharmacokinetics during pregnancy: a sub-study analysis of the HPTN 084 open label extension study. In Munich, Germany 2024

    Notes from: Focus on CAB for PrEP Implementation Research and Surveillance during Pregnancy and Breastfeeding

    		 REMAINING GAPS TO BE ADDRESSED
    Additional analysis on whether a dose adjustment may be needed during pregnancy

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    CAB has been found to be safe and efficacious in individuals over 35 kg, regardless of age.The HPTN 084-01 sub study found that CAB was safe and tolerable in cisgender women under 18, with 100% adherence to injection visits; 94% chose CAB in the OLE phase.    		 LEARN MORE
    CAB LA for HIV Prevention in African Cisgender Female Adolescents    		 REMAINING GAPS TO BE ADDRESSED
    Additional data on use of CAB in people of all genders under the age of 18.

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    HPTN 083 demonstrated that CAB is safe and effective for trans women.    		 LEARN MORE
    Landovitz Raphael J., Donnell Deborah, Clement Meredith E., Hanscom Brett, Cottle Leslie, Coelho Lara, et al. Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women. New England Journal of Medicine. 2021 Aug 11;385(7):595–608    		 REMAINING GAPS TO BE ADDRESSED
    Data on use of CAB by trans men and non binary individuals.
    Initial findings suggest feminising gender affirming hormone therapy (GAHT) does not impact CAB concentration. Slides from: Bridging from the HPTN 083 and 084 Open Label Extensions to Implementation, March 2023 Data on impact of CAB on feminising GAHT and data on interactions between CAB and masculinising GAHT.

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    HPTN 083 and 084 did not include individuals who reported injection drug use in the past 90 days, though on-study injection behaviour did not lead to discontinuation.    		 REMAINING GAPS TO BE ADDRESSED
    Data on use of CAB by people who inject drugs

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    40% of participants in HPTN 084 reported transactional sex in the one month prior to enrolment; 20% of participants in the qualitative sub-study self identified as sex workers and noted they liked the discretion provided by CAB.    		 LEARN MORE
    Slides from: Bridging from the HPTN 083 and 084 Open Label Extensions to Implementation, March 2023    		 REMAINING GAPS TO BE ADDRESSED
    Additional data on use of CAB by sex workers to answer questions on implementation and generate additional evidence on uptake and acceptability.

    Service Delivery Models

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    The SEARCH study effectively offered choice of CAB for PrEP, oral PrEP, and PEP across three settings: outpatient facilities, antenatal clinics, and community health workers going door-to-door.    		 LEARN MORE
    Webinar: Discussing Early Results from the SEARCH Dynamic Choice Study    		 REMAINING GAPS TO BE ADDRESSED
    Additional data on CAB delivery via a variety of service delivery models.

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    Participants in HPTN 083/084 were screened for abnormal levels of aspartate aminotransferase (AST) and alanine transaminase (ALT) at each visit, with 2.1% in HPTN 083 and less than 1% in HPTN 084 discontinuing due to concerns around liver function; these rates were the same in each arm of their respective studies and similar to what has been found in oral PrEP trials.

    Participants who contracted Hepatitis C Virus (HCV) during the trials were not automatically discontinued though most had to discontinue due to LFT results.

    		 REMAINING GAPS TO BE ADDRESSED
    Additional data to confirm the liver safety of CAB for PrEP and whether there are any groups that may require monitoring, such as those with HCV or heavy alcohol use.

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    Participants in HPTN 083/084 were screened for syphilis, chlamydia, and gonorrhoea (both studies) and trichomonas (084 only) at the start of the trials and OLEs and every 24 weeks thereafter; symptoms or an exposure could also trigger testing at any time.

    The WHO issued guidance in September 2022 on optimal screening algorithms for PrEP programmes.

    		 REMAINING GAPS TO BE ADDRESSED
    WHO's Implementation tool for pre-exposure prophylaxis of HIV infection - Integrating STI services    		 REMAINING GAPS TO BE ADDRESSED
    Additional data to inform strategies to increase access to laboratory-based STI testing.
    STI rates were not higher in the CAB arms of HPTN 083 and 084, though in general HPTN 084 found very high STI rates amongst AFAB participants. Optimal strategies to address high rates of STIs within PrEP programmes.

    Costing

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    This evidence is being collected across multiple implementation science studies but is not yet available.    		 REMAINING GAPS TO BE ADDRESSED
    Data on cost of CAB delivery via a variety of service delivery models.

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    Cost-effectiveness studies using evidence from HPTN 083 and 084 suggest that CAB for PrEP can be cost-effective, particularly if priced at one to two times the costs of oral PrEP.    		 LEARN MORE
    What can modelling tell us about the scale-up of CAB for PrEP?    		 REMAINING GAPS TO BE ADDRESSED
    Data on cost effectiveness of CAB delivery via a variety of service delivery models.

    EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES
    The degree to which PrEP use corresponds with seasons of risk will have a significant impact on cost-effectiveness, though this requires following up with those who are no longer coming in for clinical care which is challenging.    		 REMAINING GAPS TO BE ADDRESSED
    Optimal strategies to collect information on PrEP usage and seasons of risk.