Programmatic considerations for long-

acting HIV treatment regimens

Snigdha Vallabhaneni, MD, MPH
HIV Care and Treatment Branch
Division of Global HIV and TB

March 30th , 2023

Division of Global HIV & TB
Background: Why long-acting?
1. A small, but sizable, population will not suppress on oral regimens.
• Young people, PWID, those with psychiatric illness, mobile populations may need alternatives to
taking daily pills
2. Some who suppress on a daily oral regimens may still prefer other treatment modalities.
• Pill fatigue
• Privacy (half of PLHIV engage in at least one concealment behavior)
3. “Low touch” approaches as we look towards sustainability of the HIV response
• MMD, community pharmacies, drug distribution centers have been part of this approach
• Can long-acting be part of this “low touch” approach?

Division of Global HIV & TB 2

Cabotegravir + Rilpivirine
• Cabotegravir is an INSTI like DTG
• Rilpivirine is an NNRTI like EFV
• Available in oral and long-acting formulations
• Dosing every 4 weeks or 8 weeks
• Oral lead-in (?) + need for bridging with oral regimen
if missed or late injection
• Cold chain required, safe injection disposal, not self-
administered (buttock injection)

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Cabotegravir + Rilpivirine Efficacy
• Studies evaluating efficacy in:
– ART naïve PLHIV, suppressed on initial oral regimen
– ART experienced PLHIV but suppressed at the time of switching to injectable
– Q4 week vs Q8 week dosing
– With an oral-lead in vs direct-to-inject in virally suppressed patients
– Non-suppressed PLHIV with adherence challenges

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Efficacy in ART-naïve PLHIV (FLAIR)
• ART naïve, no HBV coinfection, no baseline NNRTI mutations
• 20 weeks of daily oral induction therapy with DTG/ABC/3TC, achieved VS
• Randomized ~600 participants at 20 weeks to CAB/RPV (with 1 month oral
lead-in followed by monthly injections) vs DTG/ABC/3TC
At 48 weeks: 100 93.6 93.3
80

Non-inferiority 60
maintained at 40
96 weeks
20 LA CAB + RPV
2.1 2.5 4.2 4.2 Continued BL ART
0
Virologic Virologic No Virologic
Nonresponse Success Data
(≥50 c/mL) (<50 c/mL)

Division of Global HIV & TB Orkin, N Engl J Med 2020; 382:1124-1135;; Orkin, Lancet HIV. 2021;8:e185; Graph from Clinical Care Options 5
Efficacy in ART-experienced, virally suppressed (ATLAS)
• ART-experienced (2NRTIs + either PI, INSTI, or NNRTI), no history of VF and
suppressed for at least 6 months
• Randomized ~600 participants to CAB/RPV (with 1 mo oral lead-in followed
by monthly injections) vs original oral regimen
At 48 weeks: 100 92.5 95.5
80
Non-inferiority 60
maintained at 96
weeks 40
20 LA CAB + RPV
1.6 1.0 5.8 3.6
0 Continued BL ART
Virologic Virologic No Virologic
Nonresponse Success Data
(≥50 c/mL) (<50 c/mL)

Division of Global HIV & TB Swindells, NEJM. 2020;382:1112; . Swindells, AIDS. 2022;36:185 Graph from Clinical Care Options 6
Every 4 weeks vs every 8 weeks (ATLAS 2M)
• PLHIV on oral ART for at least 6 months without history of virological failure
and documented VL<50 or completed 52 weeks of ATLAS study
• Randomized ~1000 PLHIV to Q4 vs Q8weeks
At 48 weeks: 100 94 93

80

60

40

20 LA CAB + RPV Q8weeks

2 1 4 6
LA CAB + RPV Q4weeks
0
Virologic Virologic No
Nonrespon Success Virologic
se (≥50 (<50 c/mL) Data
c/mL)
Division of Global HIV & TB Overton,. Lancet. 2021;396:1994; Graph from Clinicall Care Options 7
Every 4 weeks vs every 8 weeks (ATLAS 2M)
• PLHIV on oral ART for at least 6 months without history of virological failure
and documented VL<50 or completed 52 weeks of ATLAS study
• Randomized ~1000 PLHIV to Q4 vs Q8weeks
At 152 weeks:
Confirmed
virologic
failure
occurred in 11
patients in the
Q8 weeks and
2 in the Q4
week arms;
11/13
developed CAB
or RPV
resistance
mutations

Division of Global HIV & TB Overton, CROI 2022. Abstr 479. 8

Direct to inject for suppressed (FLAIR Extension study)
• FLAIR extension study
Virologic Outcomes at Wk 124
– Participants on DTG/ABC/3TC arm Following Switch to LA IM CAB + RPV at
achieving virologic suppression in Wk 100
20-wk induction phase could switch to 100
monthly CAB/RPV at
80
Wk 100

Patients (%)
– ~200 Switchers randomized to groups 60
with or without an oral CAB + RPV
lead-in 40

– Similar adverse event profile 20

0
Virologic Virologic No Virologic
Nonresponse Suppression Data

No oral lead-in
Oral lead-in

Division of Global HIV & TB Orkin, Lancet HIV. 2021;8:e668.; Graph from Clinical Care Options 9
More data among suppressed PLHIV (SOLAR)
• PLHIV suppressed on oral regimen of BIC/TAF/3TC
• Randomized ~600 participants to continue BIC/TAF/3TC vs CAB/RPV Q2mos

Division of Global HIV & TB Ramgopal, CROI 2023 Abstract 191 10

Efficacy in treatment experienced, including unsuppressed patients
• Enrolled 133 participants in a public clinic in San Francisco; Patients receive
psychosocial support, wrap-around services
• Participants needed to be willing to get injectable therapy (Q4 weeks) and not have
a history of RPV of CAB mutations.
– 76 with virologic suppression
– 57 with viremia
• 76% of injections were on time
• At a median of 26 weeks:
– all 76 with previous suppression suppressed
– 55 of 57 with previous viremia suppressed
▪ 2 with non-suppression developed resistance
• Note that another abstract presented at CROI on predictors of viremia among those
who switch to CAP/RPV, previous history of detectable VL was associated with
detectable VL on CAB/RPV.

Gandhi et al, CROI 2023; Abstract #518; Patel et al, CROI 2023 Abstract #516
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Factors associated with virologic failure on CBV/RPV
Data from 1039 adults naive to long-acting CAB/RPV combined from various trials
1.25% overall CVF on CAB/RPV

Cuttrell et al, AIDS 2021, 35:1333–1342 12

Factors associated with virologic failure on CBV/RPV
Data from 1039 adults naive to long-acting CAB/RPV combined from various trials
1.25% overall CVF on CAB/RPV

Cuttrell et al, AIDS 2021, 35:1333–1342 13

Summary of evidence
• Fairly good evidence of effectiveness in virally suppressed patients
– Overall 1.4% virologic failure rate for CBV/RPV across all trials
– Effective in ART naïve (but suppressed initially on oral regimen) and treatment
experienced patients with no prior history of VF or INSTI/RPV mutations
– Oral lead-in does not seem necessary in suppressed patients
– Q8 week seems equivalent to Q4 week dosing in suppressed patients, but ?some
concern about efficacy with Q8 dosing in the long term
• Promising in unsuppressed patients; caveat are that study was small (n=~50
patients), genotyping results were available before starting patients on
injectable therapy, and there was lots of adherence and other support
available

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Capsid inhibitor- Lenacapavir (Gilead)
Subcutaneous, could be self-administered
q 6 months
Retains full activity against NRTI-, NNTRI, PI-, and
INSTI-resistant HIV-1 in vitro

CAPELLA: (phase 2/3): Lenacapvir for highly treatment

experienced with MDR HIV
• Need to use with optimized backgroud regimen
• At 26 weeks, 80% viral suppression
Currently, no companion long acting drug
CALIBRATE: Phase 2 for ART-naive
• SC LEN + F/TAF arms VS <50cps/ml: 93% (n=98/105)
vs
• oral LEN + F/TAF arm VS <50cps/ml: 94% (n=49/52)
Division of Global HIV & TB Segal-Maurer, NEJM 2022; 386:1793-1803; Gupta, IAS 2021 Abstract OALB0302 15
NRTTIs (reverse transcriptase translocation inhibitor)- Islatravir (Merck)

• Is available as an oral regimen (weekly

dosing)
• Trials initiated in combination with daily
doravirine (DOR+ISL)
• Held in 2021 due to concern for reduced
total lymphocyte and CD4 counts (dose
dependent)
• Resumed in 2022, but being studied as
weekly drug along with lenacapravir

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Challenges with implementation (for CAB/RPV)
• Trials did not include pregnant women and children and not done in LMICs
• Trials screened for baseline hep B status and pre-treatment drug resistance
(same issue as with dual therapy), but allowed for K013N (does not effect
RPV).
– Would this be possible in LMICs?
– RPV resistance is higher in areas with subtype C (12-15% in sub-Saharan African
countries) and lack of availability of pre-treatment screening in many PEPFAR countries
• In trials, a window of +/- 7 days was allowed. Missed doses beyond 7 days
required oral bridging packs to next injection.

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Other implementation considerations (for CAB/RPV)
• Service delivery considerations
– Frequency of visits to Q2 months rather than current paradigm of Q6 months MMD
– Q2 months may not be adequate for those with viremia at start of therapy
– Cadres of HCWs needed to provide injections and safe disposal of needles
– Ability to provide care in the community?
• Product availability
– CAB-LA production for PrEP is currently being prioritized over CAB for treatment
– CAB is still undergoing licensing and selection of companies for generic production
– RPV-LA not licensed for generic production yet
– Projected availability ~2027
– Pricing unknown, but projected at ~$30-40 for 6 shots/year of CAB component.

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Where do we go from here: Long-acting regimens for treatment in
PEPFAR
• Implementation of CAB-LA for PrEP will provide important programmatic lessons to
inform use of long-acting for treatment
– PEPFAR is piloting use of CAB-LA in some places as part of this year’s COP
• Long-acting ARVs for treatment with generic pricing is likely at least 3-5 years away
for LMIC
• Baseline hepatitis B testing and genotype to rule-out pre-treatment drug resistance
make implementation more challenging
• Patients with adherence challenges and virologic failure, are likely to benefit the
most from long-acting regimens, but most studies require previous VS to start long-
acting and data in non-suppressed are very limited
• How often would viral loads needs to be done and need for genotyping for those
failing CAB/RPV given concerns about resistance
• Currently, lenacapavir is the only q6month long acting ARVs, but it hasn’t been
tested in combination with other long-acting drugs, so a full 6-month regimen
continues to be unavailable.

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Questions for discussion
• Who would benefit from it?
– Pill fatigue? Unsuppressed?
• Hepatitis B and baseline genotyping testing feasible before starting therapy?
• Cold chain and safe needle disposal?
• Currently, many patients are on MMD and come to clinics every 3 or 6
months. What would monthly/bimonthly injection requirement mean in
terms of program adaptations?
• What about staffing? Would the cadre of HCWs need to change in order to be
able to deliver injections safely?
• What would injection-based therapy mean in terms of descentralization of
care? Could community-based models (similar to community distribution points)
take on an injection-based system (or implant-based)?
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Thank you