Gabriel Wagner, MD Associate Clinical Professor Division of Infectious Diseases & Global Public Health Department of Medicine University of California, San Diego

1. HIV & Global Health Rounds
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physicians, and researchers. The goal of these presentations is to
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HBV, HCV, TB, and other infectious diseases of global significance.
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2. Updates in HIV Prevention
from virtual CROI 2021
Gabriel Wagner, MD
Associate Clinical Professor
Infectious Diseases & Global Public Health

3. Disclosures
• None

4. vCROI 2021 Talks on HIV Prevention
• Jean-Michel Molina: Advances in Biomedical Prevention of HIV
– Program Committee Workshop for New Investigators and Trainees
• Marina Caskey: HIV-1 bNAbs: Looking Ahead
– Plenary Session
• Linda-Gail Bekker: Sustained Delivery and Long Acting Agents for
Prevention of HIV-1
– Plenary Session
• Interactive Session Panel: Can Efficacy Be Translated into
Effectiveness?
– Francois Venter, Nittaya Phanuphak, Charles Flexner, Hyman Scott

5. PrEP Regimens
• Topical
– Dapivirine ring
• Oral
– TDF/FTC
– TAF/FTC
– Islatravir
• Parenteral
– Cabotegravir LA IM
– Lenacapavir SC
– Implants (Islatravir, cabotegravir, TAF)
– Broadly neutralizing antibodies (bNAbs)

6. Dapivirine Ring

7. Dapivirine Vaginal Ring
1,959 young women, median age 25.9 years
South Africa and Uganda
31% reduction in HIV-incidence HR: 0.69 (95% CI: 0.49-0.99; p=0.04)
Nel et al., NEJM 2016
2,629 women, mean age 27 years in Sub-Saharan Africa
Reduction in HIV incidence: 27% (95% CI: 1-46, p=0.046)
Reduction in HIV incidence: 37% after exclusion of two sites
Baeten et al., NEJM 2016
•Randomized double-blind study
•Dapivirine vaginal ring vs placebo
•Flexible, silicone matrix
•Ring with 25mg Dapivirine
•Self-inserted every 4 weeks
•Releases drug into vaginal tissue
Molina JM, vCROI 2021

8. Open-Label Extension Studies
with Dapivirine Ring
• 941 women enrolled, median age 30 years
• South Africa and Uganda
• >83% self-report adherence to ring
• Observed HIV incidence: 1.8 per 100 PY
(95% CI: 1.1-2.6)
• 62% reduction in HIV incidence compared
to expected incidence based on the Ring
study (4.7 per 100 PY in placebo arm)
Nel et al., Lancet HIV 2021
• 1,456 women enrolled, median age 31
years
• Malawi, South Africa, Uganda, Zimbabwe
• Ring acceptance> 79% at each visit
• Observed HIV incidence: 2.7 per 100 PY
(95% CI: 1.9-3.8)
• 39% reduction (95% CI 14-65) in HIV
incidence compared to an expected
incidence based on ASPIRE (4.4 per 100 PY
in placebo arm
Baeten et al., Lancet HIV 2021
Molina JM, vCROI 2021

9. Bekker LG, vCROI 2021

10. Next Steps with
Dapivirine Vaginal Rings
• EMA approval July 2020 for women in high HIV burden areas when
oral PrEP is not used or not available
• WHO recommendation in January 2021 for DPV-VR as a new choice
for HIV prevention for women at substantial risk of HIV infection
• More studies ongoing:
– 300 adolescent girls and young women: REACH study in South Africa,
Uganda, Zimbabwe
– 750 pregnant women: DELIVER study in South Africa, Uganda, Malawi,
Zimbabwe
– Breast-feeding women: B-PROTECTED in Africa
• Multipurpose technologies for contraception and HIV prevention:
rings with dapivirine and levonorgestrel
Molina JM, vCROI 2021

11. Phase 1 PK, Safety, and Acceptability Study
of 3-Month Dapivirine Vaginal Rings
• MTN-036/IPM 047
• Phase 1, three-arm, randomized (1:1:1) trial:
– 25mg DPV ring
– 100mg DPV ring
– 200mg DPV ring
• 49 HIV-uninfected women and those assigned female at birth
– Healthy
– Age 18-45
• Two study sites:
– University of Alabama at Birmingham
– San Francisco Department of Public Health
Liu A et al., vCROI 2021
Replaced every 4 weeks for 8 weeks, then worn for an additional 5 weeks
Worn continuously for 13 weeks

12. Phase 1 PK, Safety, and Acceptability Study
of 3-Month Dapivirine Vaginal Rings
• Majority of adverse events were mild (79%) or moderate (21%)
– One grade 3 AE was unrelated
• Most participants liked the rings (Median 8 on 10-point Likert Scale)
• Most were likely to use the ring if effective (Median 9)
Liu A et al., vCROI 2021

13. Oral PrEP

14. IPERGAY: Sex-Driven iPrEP
Molina JM, vCROI 2021
4 pills of TDF/FTC taken over 3 days to cover one sexual intercourse

15. Effectiveness of On Demand PrEP with
TDF/FTC in MSM in France & Canada
Molina JM et al., NEJM 2015

16. PrEP with Daily or On Demand
TDF/FTC among MSM
Molina JM et al., vCROI 2021

17. Daily vs On-Demand Oral PrEP
An Update of the ANRS Prevenir Study
Molina JM et al., vCROI 2021
• Primary objective could not be assessed because of COVID-19
• 3,067 (98.5% MSM), 49.5% On-Demand
– Significantly fewer condomless acts and fewer sex partners at baseline
• Only 3 patients discontinued permanent PrEP due to GI AEs (2 Daily and 1 On-
Demand)
• All-grade ALT elevation incidence 22.22 (95% CI: 20.44-24.11) in Daily Arm and
18.33 (95% CI: 16.70-20.06) in On-Demand Arm (IRR 1.21; 95% CI: 1.07-1.37)
• Low incidence of Creatinine Clearance <50 ml/mn in both arms
– Daily Arm (0.54; 95% CI: 0.30-0.91) and On-Demand Arm (0.55%; 95% CI: 0.30-0.92)
• High incidence of bacterial and viral STIs (HepC)

18. Trends in TDF/FTC and F/TAF prescriptions
in the US (2014-2020)
Hoover K et al., CDC, vCROI 2021
• IQVIA Longitudinal Prescription
• 36.3% of new PrEP users after
October 2019 were prescribed F/TAF
• 28.5% of 228k F/TDF users switched
to F/TAF
• PrEP users who switched to F/TAF
more likely to be:
• Older
• Male
• Hispanic/Latino
• And less likely to be
• Cash payers
• Other payers

19. PrEP Trends in 48 EHE urban jurisdictions by
FQHCs vs non-FQHCs, 2014-2019
• IQVIA Longitudinal Prescription: PrEP Users and Providers
• Overall number of PrEP users increased, but more so among FQHCs
Henny K et al., CDC, vCROI 2021

20. M-Cubed app to improve HIV prevention and care
outcomes in MSM: Results of an RCT
Sullivan P et al., CDC, vCROI 2021
• Built on Social Cognitive Theory
• Forerunner app demonstrated
acceptability and usability
• Prevention messages
• Condoms, PrEP, STIs, HIV Care
• Infographics and short videos
• Core services
• Establish testing & frequency
• Risk screening for PrEP & nPEP
• Service locators for PrEP & testing
• Information about prevention
• Commodity ordering
• Condoms & lubricant
• HIV self-test kits
• STI specimen self-collection test kits

21. M-Cubed app increased HIV testing
and PrEP use among higher-risk MSM
Sullivan P et al., CDC, vCROI 2021
• Randomized 1:1 app to delayed onset app access
• Enrollment: Atlanta, Detroit, NYC
• 1,220 overall: 427 HR HIV-, 410 LR HIV-, 383 LWH
• Higher risk HIV negative
• Increased HIV testing immediate post
• Increased PrEP use 3 months post
• Lower risk HIV negative
• No significant effects
• Living with HIV
• No significant effects

22. Novel PrEP Agents

23. Islatravir: A New Potent and Long-Acting
Antiretroviral Agent
• Nucleoside reverse transcriptase translocation inhibitor
• Potent antiviral activity with low in vitro IC50 1.5nM and
activity against NRTI-resistant HIV-1 strains
• Single-dose oral ISL associated with reduction in plasma
HIV-1 RNA without emergence of viral resistance
• Robust viral load decline associated with ISL-TP
concentrations as low as 0.05 pmol/106 cells
• Long ISL-TP half-life ~120h in healthy adults
• ISL-TP concentrations in rectal and vaginal tissue similar
to PBMC concentrations at steady state
• Protects against SHIV infection in a rectal challenge
Rhesus macaque model (Markowitz et al., JID 2020) Schurmann D et al., Lancet HIV 2020
Molina JM, vCROI 2021

24. Double-Blind Randomized Placebo Controlled
Study of Monthly Oral Islatravir for PrEP
Hiller et al., HIV R4P 2021 virtual 01363
Observed mean (SD) ISL-TP concentration-time profile in PBMCs
Overlaid on population PK model simulated median (95% PI) ISL-TP concentrations
ISL 60mg QM ISL 120mg QM
ISL-TP trough concentrations following 60mg or 120mg QM doses
were above the pre-specified PK threshold of 0.05pmol/106 PBMCs

25. ISL 60mg QM Oral PrEP
Clinical Development Program
Molina JM, vCROI 2021

26. Islatravir Implants: Intracellular ISL-TP
PK Threshold Maintained for Months
Barrett SE et al., Antimicrob Agents Chemother 2018, Matthew R. IAS 2019
• 62-mg implant will continue to release through 52 weeks
• ISL-TP should be above threshold (0.05 pmol/106 cells
• Projected concentration at 12 months: 0.076 pmol/106 cells
• Projected time at which concentration falls below 0.05 pmol/106 cells: 68-70 weeks (~16 months)
• Implants in development also with TAF and cabotegravir
62 mg Implant 62 mg Implant: Simulations for 1 year
Molina JM, vCROI 2021

27. Lenacapavir: First in Class Long-Acting
HIV Capsid Inhibitor for Treatment and Prevention
• Small molecule which disrupts functions of HIV capsid protein
• High potency: Antiviral activity at very low doses (pM range) and no cross-resistance with approved drugs
• Low in vivo systemic clearance
• Slow release kinetics from the subcutaneous injection site
Link JO et al., Nature 2020; 584: 614-8
Molina JM, vCROI 2021

28. Lenacapavir Antiviral Activity and Pharmacokinetics
Begley R et al., AIDS 2020. Abstract PEB0265
Link JO et al., Nature 2020; 584: 614-8
• Potent antiviral activity with a single SC injection in HIV-infected untreated patients with maximum HIV-
1 RNA reduction seen at mean concentrations ≥ 4.4 ng/mL (IQ > 1.1)
• Lenacapavir 900 mg every 6 months used in phase 3 treatment and prevention trials: half-life > 50 days
with target concentrations sustained for > 24 weeks
Molina JM, vCROI 2021

29. Lenacapavir Prevention Trial in Women
• Another trial planned in MSM and TGW vs daily TDF/FTC in 3,000 in USA and South Africa
Molina JM, vCROI 2021

30. Long-acting HIV capsid inhibitor effective as PrEP in
SHIV Rhesus macaque model
Bekerman E et al., vCROI 2021

31. Cabotegravir
GSK126744 Long Acting Integrase Inhibitor
Favorable attributes for PrEP:
• High genetic barrier to resistance
• PK profile: half-life of 21-50 days
• Once-daily oral
• 1-2 months injectable dosing using nanosuspension formulation
Muller et al., European Journal of Pharmaceutics and Biopharmaceutics, 2011
Spreen, 7th IAS 2013; Min, ICAAC 2009
Taoda, International Congress on Drug Therapy in HIV Infection, 2012
Molina JM, vCROI 2021

32. Cabotegravir IM vs Oral TDF/FTC
for PrEP in MSM and TGW
Landovitz RJ et al., AIDS 2020, #OAXLB0101
Molina JM, vCROI 2021
4,570 MSM and TGW at 43 sites in Argentina, Brazil, Peru, US, South Africa, Thailand and Vietnam

33. PrEP with LA Injectable Cabotegravir
Highly Effective for MSM and TGW
Landovitz RJ et al., AIDS 2020, #OAXLB0101
52 HIV infections in 6,389 PY of follow up
1.4 (IQR 0.8-1.9) years median per-participant follow-up
Molina JM, vCROI 2021

34. Laboratory Analysis of HIV infections in HPTN 083
Landovitz RJ et al., vCROI 2021
Post-hoc characterization of 58 cases of HIV infection in HPTN 083
• Concentrations of CAB TFV in plasma and TFV-DP in DBS by LCMS
• 4th Gen Ag/Ab test, discriminatory test, and RNA assays.
• Drug resistance testing if HIV RNA >500 copies/mL
Group A (baseline infections): HIV positive at study enrollment
Group B: No recent CAB exposure
Group C: Infection detected during oral lead-in
Group D: Infection identified despite on-time CAB injections

35. Laboratory Analysis of HIV infections in HPTN 083
Landovitz RJ et al., vCROI 2021
In post-hoc analysis, 1 incident infection in the CAB arm was reclassified as a
baseline infection; 1 additional baseline infection was also identified

36. Laboratory Analysis of HIV infections in HPTN 083
Landovitz RJ et al., vCROI 2021
Among 12 incident infections in the CAB arm:
• 5 had no recent CAB dosing (during “pharmacokinetic tail”)

37. Laboratory Analysis of HIV infections in HPTN 083
Landovitz RJ et al., vCROI 2021
Among 12 incident infections in the CAB arm:
• 5 had no recent CAB dosing (during “pharmacokinetic tail”)
• 3 occurred in the oral lead-in phase (1 had no CAB detected)

38. Laboratory Analysis of HIV infections in HPTN 083
Landovitz RJ et al., vCROI 2021
Among 12 incident infections in the CAB arm:
• 5 had no recent CAB dosing (during “pharmacokinetic tail”)
• 3 occurred in the oral lead-in phase (1 had no CAB detected)
• 4 occurred despite on-time CAB injections and targeted CAB
concentrations
• evaluation of correlates of protection is ongoing

39. Laboratory Analysis of HIV infections in HPTN 083
Landovitz RJ et al., vCROI 2021
Among 12 incident infections in the CAB arm:
• 5 had no recent CAB dosing (during “pharmacokinetic tail”)
• 3 occurred in the oral lead-in phase (1 had no CAB detected)
• 4 occurred despite on-time CAB injections and targeted CAB
concentrations
• evaluation of correlates of protection is ongoing
Five of 16 infections in the CAB arm had integrase RAMs (Q148R or Q148K
with accessory mutations, or R263K), 1 also had NNRTI RAM
• 1 had NNRTI RAMs only and 1 had NNRTI RAMs along with NRTI RAMs

40. Laboratory Analysis of HIV infections in HPTN 083
Landovitz RJ et al., vCROI 2021
Among 12 incident infections in the CAB arm:
• 5 had no recent CAB dosing (during “pharmacokinetic tail”)
• 3 occurred in the oral lead-in phase (1 had no CAB detected)
• 4 occurred despite on-time CAB injections and targeted CAB
concentrations
• evaluation of correlates of protection is ongoing
Five of 16 infections in the CAB arm had integrase RAMs (Q148R or Q148K
with accessory mutations, or R263K), 1 also had NNRTI RAM
• 1 had NNRTI RAMs only and 1 had NNRTI RAMs along with NRTI RAMs
CAB-LA can delay detection of infection using standard HIV testing algorithms
• Oral lead-in will be optional in 083 OLE
• Use of VL testing as a primary screen

41. PrEP with LA Injectable Cabotegravir
Highly Effective for Women
Delany-Moretllwe S et al., HIV R4P virtual; Jan 2021 LB 1479
HIV, pregnancy testing and safety assessments at each product administration visit; additional post injection safety visits
Real-world adherence counseling support aligned with national guidelines
Molina JM, vCROI 2021

42. PrEP with LA Injectable Cabotegravir
Highly Effective for Women
Delany-Moretlwe S et al., HIV R4P virtual; Jan 2021 LB 1479
38 HIV infections in 3,223 women, median age 26 years
Botswana, Eswatini, Kenya, Malawi, Uganda, Zimbabwe
Molina JM, vCROI 2021

43. Adherence to Pills and Injections
Delany-Moretlwe S et al., HIV R4P virtual; Jan 2021 LB 1479
• Both products safe and well tolerated
• No discontinuation due to injection site reactions
• Similar pregnancy outcomes
Molina JM, vCROI 2021

44. Bekker LG, vCROI 2021

45. Broadly neutralizing monoclonal antibodies (bNAbs)

46. Broadly Neutralizing mAbs (bNAbs) in Development
for Treatment and Prevention of HIV
Wu X. et al., Science 2010; Mascola JR et al., Nat Medicine 2000; Gautam R et al., Nature 2016
• VRC01 (IgG1) targets conserved region of CD4-binding site of HIV-1 envelope glycoprotein with
broad in vitro neutralization capacity against all major circulating HIV-1 subtype
• VRC01 can prevent HIV/SHIV transmission in animal models

47. The AMP Studies: Phase 2b Proof of Concept
Trials to Test Efficacy of VRC01 to Prevent HIV
Acquisition
Two harmonized protocols:
• HVTN 704/HPTN 085 (2,700 MSM and TGW in Americas & Europe)
• HVTN 703/HPTN 081 (~1,900 women in sub-Saharan Africa)
• Placebo controlled trial of VRC01 mAb (IV) every 2 months
• Both trials opened April/May 2016
Michel, vCROI 2021

48. VRC01 achieved prevention efficacy against
neutralization sensitive viruses
Corey L et al., HIV R4P virtual; Jan 2021 HY01.01LB
• VRC01 showed overall prevention efficacy of only 18.1%
• Prevention can be achieved via bNAb
However, it is dependent on neutralization sensitivity of
circulating strains (only 30% VRC01 sensitive)
• In vitro neutralization assays can predict outcome
But predictions based on TZM-bl assays against
pseudoviruses were about 1 log “off” from required in
vivo sensitivity against “real viruses”
• Viruses from placebo arm tested for other bNAbs – triple
combination can achieve coverage of 90%
Caskey, vCROI 2021

49. Reminiscent of a finding from an HIV-1 superinfection study…
Monoinfection Pre-superinfection
Individuals who would become superinfected had lower NAb responses to tier 1 viruses.
“…NAb response of monoinfected participants may have been sufficient to decrease
susceptibility to HIV-1 superinfection”
Wagner et al., JVI 2017

50. AMP Studies Summary
• Proof of concept that long-acting bNAbs can prevent HIV
acquisition
• In vitro HIV-1 susceptibility to VRC01 influences preventive efficacy
(only 30% of circulating strains exhibited IC80<1μg/ml)
• A neutralization titer or Ab concentration in serum was established
as a biomarker of protection
• Viruses from VRC01 cases more resistant to VRC01 than viruses
from placebo cases (>2-fold greater IC80): immunologic pressure
• Multiple bNAbs will be needed for optimal prevention
Molina JM vCROI 2021

51. HIV bNAb Research Facilitated SARS-CoV-2 NAb Development
Mendoza et al., Curr Opinion HIV 2020
Adapted from Caskey, vCROI 2021

52. #VaccineEquity #NoVaccineApartheid

54. Week 96 Efficacy and Safety of Long-Acting
Cabotegravir + Rilpivirine Every 2 Months: ATLAS-2M
Jaeger et al., vCROI 2021

55. Week 96 Efficacy and Safety of Long-Acting
Cabotegravir + Rilpivirine Every 2 Months: ATLAS-2M
Jaeger et al., vCROI 2021

56. Week 96 Efficacy and Safety of Long-Acting
Cabotegravir + Rilpivirine Every 2 Months: ATLAS-2M
Jaeger et al., vCROI 2021