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		The impact of INSTI resistance following CAB exposure on dolutegravir (DTG) as a first-line treatment
If HIV is not detected quickly after a CAB for PrEP failure, INSTI resistance can develop.		• Whether RNA testing can be useful clinically for detecting CAB for PrEP failure before INSTI resistance develops, and if so whether and how it can be feasible to implement • Optimal strategies to manage and treat current and former CAB users who have seroconverted
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 testing should be sufficient for initiation and continuation; while RNA testing may detect some infections earlier there are a range of barriers, including costs, lengthy turnaround times, and lack of regulatory approvals, so it may not be feasible in many settings; modelling suggests CAB still has a population-level benefit on HIV-related mortality despite increases in INSTI resistance, with limited impact of RNA testing	LEARN MORE What can modelling tell us about the scale-up of CAB for PrEP?	REMAINING GAPS TO BE ADDRESSED • How barriers can be minimised to catalysing the development, testing, and regulatory approvals for more sensitive HIV diagnostics that are inexpensive, have durable supply chains, and can be done at point of care in low and middle income settings • Whether RNA testing can be useful clinically for detecting CAB for PrEP failure before INSTI resistance develops, and if so whether and how it can be feasible to implement
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
CAB for PrEP will never be as cost effective as oral PrEP if RNA testing is required	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
Viral load testing can result in false positives; the HPTN 083 and 084 trials define positive as either any single RNA measurement at greater than 200 copies per millilitre (ml) or two RNA measurements at any level		Further follow-up with participants identified as false positives in HPTN 083 and 084 to confirm accuracy of positivity criteria used

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 None to date—a subset of the PrEP Choice Investigators group is looking into harmonising indicators around patterns of use

REMAINING GAPS TO BE ADDRESSED Meaningful indicators on patterns of use

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

<!-- CATEGORY: Safety, acceptability... QUESTION: Is CAB safe, acceptable, and efficacious for pregnant and lactating populations? -->
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<td style="width: 33%; height: 200px; vertical-align: top;"><strong>EVIDENCE FROM CLINICAL, IMPLEMENTATION, AND MODELLING STUDIES</strong>
Participants in HPTN 084 who received CAB injections until a pregnancy diagnosis had residual CAB concentrations similar to non-pregnant populations, tolerated the residual CAB well, and experienced no congenital abnormalities</td>
<td style="width: 33%; height: 200px; vertical-align: top;"><strong>LEARN MORE</strong>
<a href="/wp-content/uploads/2023/01/BioPIC-IS-Meeting-CAB-for-PrEP-Research-During-Pregnancy-and-Breastfeeding-Notes-Public.pdf">Notes from: Focus on CAB for PrEP Implementation Research and Surveillance during Pregnancy and Breastfeeding</a></td>
<td style="width: 33%; height: 200px; vertical-align: top;"><strong>REMAINING GAPS TO BE ADDRESSED</strong>
How well CAB is tolerated if it is continued throughout pregnancy, what dose adjustment may be needed during pregnancy, and association with adverse pregnancy outcomes, including more rare outcomes</td>
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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.

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.

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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.

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.