The Data-Free Zone: �Tough Cases in HIV Prevention, 2021 Edition

Raphael J. Landovitz, MD, MSc

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Professor of Medicine

University of California Los Angeles�Los Angeles, California

Financial Relationships With Ineligible Companies (Formerly Described as Commercial Interests by the ACCME) Within the Last 2 Years

Dr Landovitz has served on scientific advisory boards for Gilead Sciences, Inc, and Merck & Co, Inc. (Updated 9/20/21)

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Learning Objectives

After attending this presentation, learners will be able to:

• Describe options for PrEP in patients with decreased kidney function and low bone mineral density
• Describe the state of the science on STI prevention strategies
• Describe recent data on the safety and efficacy on injectable PrEP options

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Effectiveness of TDF/FTC in Randomized

Clinical Trials

Landovitz RJ et al. AIDS 2020, #OAXLB0101

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“PrEP 2.0”: Trials of Novel PrEP Agents

Incidence rate

0.30%

Incidence rate

0.16%

DISCOVER

(TDF/FTC) (TAF/FTC)

Landovitz RJ et al. AIDS 2020, #OAXLB0101

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Effectiveness of Daily TDF/FTC in Clinical Trials

SS Abdool Karim, personal communication

• Cr Cl ≥ 60
• No history of osteopenia/osteoporosis/non-traumatic fractures
• HBsAg negative
• Patients come in every 3 months for safety labs, STI testing, and adherence checks prior to refills
• Limited medical co-morbidities

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PrEP is straightforward when…

• A 50-year-old man with type 2 DM, CKD 3, and hypertension recently started a new relationship with an HIV-infected man and is seeking advice on how best to avoid HIV infection
• His partner admits to struggling with taking ART regularly, but says he is “mostly adherent” and does not like to use condoms
• One month after initiating PrEP, Cr Cl dropped to 55 mL/min
• UA is normal and safety labs are rechecked and show Cr Cl is further decreased to 50 mL/min

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Case 1:

Beans, beans and nothing but beans

Your best advice regarding his PrEP is:

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ARS Question #1

1. Continue daily oral TDF/FTC, recheck in 1 month
2. Switch to event-based (“2-1-1”) dosing of TDF/FTC
3. Dose reduce TDF/FTC to 3 x week
4. Switch to TAF/FTC daily
5. Something else

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• Longitudinal clinical cohort study (2014-2017)
• PrEP users (n=172 over 689 visits)
• Baseline creatinine <1 year before PrEP initiation and ≥1 follow-up creatinine
• Mean Cr Cl change: -6 mL/min at month 24
• No cases of elevated creatinine with Cr Cl <60 mL/min
• No discontinuations of PrEP due to decline in eGRF
• Cr Cl <70 mL/min after baseline Cr Cl ≥70 mL/min (n=8)
• Recovered (n=3); remained >60 mL/min (n=5)
• Significantly associated with age ≥ 50 years and baseline Cr Cl <90 mL/min (both P<0.0001)

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Harvey M et al., AIDS Res Hum Retroviruses, 2018

Impact of Long-Term PrEP Use and Renal Function

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• iPrEx-Ole (n=1224) found a greater decline in renal function with older age
• 40–50 years: –4.2% [–2.8,–5.5]
• 50+ years: –4.2% [–2.8,–5.5]
• The likelihood of Cr Cl falling below 60 mL/min were higher in participants with a baseline Cr Cl of 90 mL/min or less.

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Gandhi M et al., Lancet, 2016

↑ Age, ↓ Baseline Cr Cl , and Adherence Associated with Declining Renal Function

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Gandhi M et al., AIDS, 2017

• The EPIC Hair study enrolled and collected hair samples for 280 PrEP Demo participants
• Drug level concentrations in hair were highly correlated with DBS concentrations
• Decline in renal function associated with higher drug level concentrations.

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↑ Age, ↓ Baseline Cr Cl , and Adherence Associated with Declining Renal Function

Estimated number of TDF/FTC doses per week

-8

-6

-4

-2

0

2

4

6

p-value for trend = 0.011

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Khan S et al., OFID, 2017

CCTG 595: PrEP Associated with Fanconi Syndrome

• 49-year-old white man, Hx kidney stones, HBV/HCV negative, no ongoing medical problems or medication use
• Mild renal impairment detected at baseline (Cr Cl: 79.9 mL/min).
• Initiated daily oral TDF/FTC-based PrEP
• 12 weeks after PrEP initiation
• 25% decrease in Cr Cl,
• Hypophosphatemia with renal phosphate wasting

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DISCOVER: A Randomized, Noninferiority Trial of F/TAF for PrEP

F/TAF dose: 200/25 mg; F/TDF dose: 200/300 mg. eGFR, estimated glomerular filtration rate.

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Study conducted in NA, �EU in cities/sites with �high HIV incidence

• 94 sites in 11 countries
• Participants: US, 60%; �EU, 34%; Canada, 7%

Eligibility required high sexual �risk of HIV

• 2+ episodes condomless anal sex �in past 12W or rectal gonorrhea/�chlamydia, syphilis in past 24W
• HIV & HBV negative, eGFR ≥60 mL/min
• Prior use of PrEP allowed

Primary efficacy endpoint: �HIV incidence

• Evaluated by rate ratio with noninferiority (NI) margin <1.62
• Expected incidence of 1.44/100 PY based on pooled studies: �iPrEx, PROUD, IPERGAY

Randomized

1:1

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Double-blinded

Active controlled

Primary analysis:

HIV incidence/100 PY

when 100% complete W48 �& 50% complete W96

MSM or TGW

participants

96 weeks

Open-label

switch

for 48 weeks

At entry and Q12W:

Adherence counseling

Prevention services

• Risk reduction counseling
• Condoms/lubricant

F/TAF QD

n=2694

F/TDF QD

n=2693

Slide courtesy of Gilead Sciences

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Incidence of HIV per 100 PY in the F/TAF and F/TDF groups and IRR (F/TAF divided by F/TDF). Error bars represent 95% CIs.

F/TAF=emtricitabine and tenofovir alafenamide. F/TDF=emtricitabine and tenofovir disoproxil fumarate. IRR=incidence rate ratio. PY=person-year.

DISCOVER: HIV Incidence

Ogbuagu O et al. Lancet HIV. 2021

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DISCOVER: Renal Safety

Ogbuagu O et al. Lancet HIV. 2021

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IPERGAY: eGFR changes not different TDF/FTC v. PBO

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• The slope of eGFR decline was not statistically different between TDF/FTC and placebo group.

Liegeon B et al., CROI, 2019

Case 2: Broken Dreams

• A 35-year-old man reports having receptive anal sex with 2-3 different partners each month, and he is eager to start PrEP
• He was diagnosed with early osteoporosis in 2015 and has a history of non-traumatic fractures.

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Your best advice is:

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ARS Question #2

1. Proceed with daily oral TDF/FTC alone
2. Initiate PrEP with TAF/FTC
3. Proceed with daily oral TDF/FTC but recommend Vitamin D and Calcium supplementation
4. Something else

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iPrEx: Bone Mineral Density Loss and Recovery

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1. Mulligan K et al., CID, 2015

2. Glidden D V et al., JAIDS, 2017

• iPrEx DXA substudy (n=498) found spine BMD decreases in the TDF/FTC group compared to the PBO group.
• Hip BMD initially decreased TDF/FTC group, but rebounded before decreasing again at Week 96

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iPrEx: Bone Mineral Density Loss and Recovery

1. Mulligan K et al., CID, 2015

2. Glidden D V et al., JAIDS, 2017

• iPrEx DXA substudy (n=498) found spine BMD decreases in the TDF/FTC group compared to the PBO group
• Hip BMD initially decreased TDF/FTC group, but rebounded before decreasing again at Week 96
• Decreases in BMD were statistically significant in those with detectable drug levels when compared to the PBO group

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iPrEx: Bone Mineral Density Loss and Recovery

1. Mulligan K et al., CID, 2015

2. Glidden D V et al., JAIDS, 2017

• iPrEx DXA substudy (n=498) found spine BMD decreases in the TDF/FTC group compared to the PBO group
• Hip BMD initially decreased TDF/FTC group, but rebounded before decreasing again at Week 96
• Decreases in BMD were statistically significant in those with detectable drug levels when compared to the PBO group
• Recovery of BMD realized between 48 and 79 weeks after discontinuing TDF/FTC.
• Similar results were noted in young African women in the VOICE substudy (MTN-003B)

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1.

BMD Loss Attenuated by Vitamin D and Calcium

• 167 HIV-infected patients initiating ART were randomized to receive vitamin D3 plus calcium (n=81) or PBO (n=86).
• Percentage of BMD change from baseline to week 48:
• Hip: -1.5 (IQR -3.2, -0.4) VS -3.2 (IQR -5.1 to -1)
• Spine: -1.4 (IQR -3.8; 0) VS -2.9 (IQR -4.8 to -1.1)
• Percentage of changes in BTM and PTH levels at weeks 24 and 48.
• Increases were attenuated in the vitamin D3 plus calcium group compared with the placebo group at 24 weeks

1. Overton TE et al., Ann. Intern. Med., 2015

2. Nanayakkara D et al., AIDS Res Hum Retroviruses, 2019

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BMD Loss Attenuated by Vitamin D and Calcium

• 167 HIV-infected patients initiating ART were randomized to receive vitamin D3 plus calcium (n=81) or PBO (n=86).
• Percentage of BMD change from baseline to week 48:
• Hip: -1.5 (IQR -3.2, -0.4) VS -3.2 (IQR -5.1 to -1)
• Spine: -1.4 (IQR -3.8; 0) VS -2.9 (IQR -4.8 to -1.1)
• Percentage of changes in BTM and PTH levels at weeks 24 and 48.
• Increases were attenuated in the vitamin D3 plus calcium group compared with the placebo group at 24 weeks
• A subset of 48 HIV-uninfected men enrolled in CCTG 595 were selected to receive VitD 4000 IU/day
• Matched 1:1 with controls based on age, race, and BMI
• Vitamin D3 supplementation with 4000 IU/day resulted in a significant reduction in the BTM P1NP compared to controls

1. Overton TE et al., Ann. Intern. Med., 2015

2. Nanayakkara D et al., AIDS Res Hum Retroviruses, 2019

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DISCOVER: Bone Safety

Ogbuagu O et al. Lancet HIV. 2021

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Case 3: �A kiss is a terrible thing to waste

• 28-year-old cisgender woman is referred for PrEP
• She was diagnosed with obesity, hypertension and sleep apnea and underwent gastric bypass surgery 6 months ago
• Since the surgery, she insists on “eating clean” and takes several vitamin supplements daily, including Vitamin A, B3, B6, E, gingko biloba, and milk thistle

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How do you instruct her to optimally implement PrEP?

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ARS Question #3

1. Daily oral TDF/FTC
2. Double dose daily oral TDF/FTC
3. On-demand “2-1-1” TDF/FTC
4. Daily oral TAF/FTC
5. Something else

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Gastric Bypass and Gastric Sleeve

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TDF PK After Sleeve-Gastrectomy in 4 HIV-infected individuals

• Decrease in absorption of tenofovir at 1 month as assessed by AUC_0—24h and C_max
• Decrease in absorption of tenofovir at 6 months as assessed by AUC_0—24h
• C_max comparable to pre-operative levels
• At 12-months, AUC_0—24h and C_max return to post-operative levels
• No available data on absorption of tenofovir in HIV-unifected individual after Sleeve-Gastrectomy.

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Muzzard L et al., Obesity Research & Clinical Practice, 2017

• TDF 600 mg QD added to background ART
• Patients were seen at baseline, W2, and W4 for clinical exam, plasma HIV-1 RNA load, liver and kidney function tests, tenofovir plasma and urine concentrations, and AE assessments
• One patient (male, 50 years old) experienced Fanconi syndrome
• W2 deceline in Cr Cl from 96 mL/min to 43 mL/min
• Proteinuria 12g/24h
• Hypophosphatemia, glycosuria

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TDF Double-Dose in Treatment-Experienced HIV-Infected Patients (n=10)

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Dominguez S et al., J. Med. Virol., 2007

Case 4: It’s a dangerous world out there

• A 55-year-old transgender woman comes regularly for PrEP follow-up and all indications suggest she is adherent to PrEP
• 4-5 male sexual partners per month; condom use inconsistent
• She has a history of recurrent rectal chlamydia, with interim documentation of clearance with appropriate treatment (you confirm dates and treatment provided)

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You tell her:

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ARS Question #4

1. If she has one more STI you will stop her PrEP
2. This is an “Occupational Hazard” of Condomless Sex
3. “America, Grow up! Use a Condom”*
4. Daily doxycycline with her daily TDF/FTC
5. Doxycycline 200 mg post-coitally up to 3 doses per week
6. Have her partners gargle with listerine before oral sex or oral-anal contact

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You thought I was

joking

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I wasn’t

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West Hollywood,

California

2012

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IPERGAY OLE: PEP with Doxycycline and STIs

• 232 ANRS IPERGAY OLE participants were randomly assigned to a doxycycline PEP group (n=116) no-PEP group (n=116)
• 73 participants presented with a new STI infections during follow-up, 28 (22% [15–32]) in the PEP group 45 (42% [33–53])
• Doxycycline PEP reduced the occurrence of a first episode of bacterial STI in high-risk men who have sex with men, but NOT gonorrhea
• Larger prospective studies needed
• Bacterial resistance
• Lowered gut bacterial diversity/Gut Microbiota Modification

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Molina J et al., Lancet, 2017

• Listerine Total Care and Cool Mint were found to significantly inhibit the growth of the tested strain of N. gonorrhoeae at dilutions of 1:2 and 1:4.
• The PBS control displayed no inhibitory effect against N. gonorrhoeae.

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Antiseptic Mouthwash Against Pharyngeal�N gonorrhoeae

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Chow E PF et al., Sex Transm Infect, 2016

In Vitro

• Men in the saline group had a higher gonorrhoea culture positivity at the tonsillar fossae
• Men in the Listerine group had a lower odds of testing positive for gonorrhoea at the tonsillar fossae

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Antiseptic Mouthwash Against Pharyngeal�N gonorrhoeae

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Chow E PF et al., Sex Transm Infect, 2016

In Vitro

Randomized Controlled Trial

Case 5: Shot through the heart (And you’re to blame)�

• 24-year-old man with a history of a severe trigeminal-neuralgia syndrome provoked by TDF/FTC PrEP on two occasions (immediately after initial dosing, and on rechallenge 1 month later)
• Identical syndrome upon immediate dosing with TAF/FTC
• Extensive neurologic work-up otherwise unrevealing
• 7 male sexual partners in the past month; engages in oral and insertive anal sex; does not use condoms

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Your best advice is:

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ARS Question #5

1. Rechallenge with daily oral TDF/FTC with MVI supplementation
2. Rechallenge with TAF/FTC daily using Vitamin B6 supplementation
3. Prescribe CAB LA + RPV LA for treatment, split it apart and use the CAB LA for prevention
4. Complete compassionate use CAB LA application until commercially available
5. I have a headache stop asking me hard questions

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Case 5: Who knew?

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HPTN 083 Study Design

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CAB

TDF/FTC

(20% Intralipid solution)

Landovitz RJ et al, NEJM, 2021.

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HIV Incidence: CAB vs. TDF/FTC

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Pharmacology and Virology of HPTN 083 Seroconversion Events

Landovitz RJ et al. NEJM 2021 Marzinke MA et al JID 2021

Changes in Weight�Median of changes from baseline (IQR)�

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HPTN 077: Over 41 weeks

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CAB +1.48 (95%CI 0.15, 2.8) kg/y

PBO +1.57 (95%CI -1.35,4.49) kg/y

p=0.95

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Landovitz RJ et al. CID 2019.

Overall

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CAB +1.30 (95%CI 0.99, 1.60) kg/y

TDF/FTC +0.31 (95%CI -0.12,-0.49) kg/y

p<0.001

Landovitz RJ et al, NEJM, 2021.

Changes in Weight�Median of changes from baseline�

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Week 0-40

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CAB +1.54 (95%CI 1.0, 2.0) kg/y

TDF/FTC -0.51(95%CI -0.80,-0.22) kg/y

p<0.001

Week 40-105

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CAB +1.07 (95%CI 0.61-1.5) kg/y

TDF/FTC +1.06 (95%CI 0.79,1.3) kg/y

p=0.93

HPTN 077: Over 41 weeks

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CAB +1.48 (95%CI 0.15, 2.8) kg/y

PBO +1.57 (95%CI -1.35,4.49) kg/y

p=0.95

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Landovitz RJ et al. CID 2019.

Landovitz RJ et al, NEJM, 2021.

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Effectiveness of PrEP in Randomized Clinical Trials

1

2

3

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6

7

1. Grant et al. NEJM. 2010.
2. Van Damme et al. NEJM. 2012.
3. Thigpen et al. NEJM. 2012.
4. Baeten et al. NEJM. 2012.

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• Marrazzo et al. NEJM. 2015.
• McCormack et al. Lancet. 2016.
• Molina et al. NEJM. 2015.

Thank you!

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Suggested Further Reading

Gandhi M et al.,

Hair levels of PrEP drugs measure adherence and are associated with renal decline among men/transwomen in an open label PrEP study. AIDS (London, England). 2017 Oct 23;31(16):2245.

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Gandhi M et al.,

Association of age, baseline kidney function, and medication exposure with declines in creatinine clearance on pre-exposure prophylaxis: an observational cohort study. The Lancet HIV. 2016 Nov 1;3(11):e521-8.

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Nanayakkara D et al.,

Effect of Vitamin D Supplementation on Bone Turnover Markers during HIV Pre-exposure Prophylaxis using Tenofovir Disoproxil Fumarate-Emtricitabine in Men who have Sex with Men. AIDS Research and Human Retroviruses. 2019 Jul 1;35(7):608-14.

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Mulligan K et al.,

Effects of emtricitabine/tenofovir on bone mineral density in HIV-negative persons in a randomized, double-blind, placebo-controlled trial. Clinical Infectious Diseases. 2015 Apr 23;61(4):572-80.

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Glidden DV et al., Brief Report: Recovery of Bone Mineral Density After Discontinuation of Tenofovir-Based HIV Pre-exposure Prophylaxis. Journal of Acquired Immune Deficiency Syndromes (1999). 2017 Oct;76(2):177-82.

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Overton ET et al., Vitamin D and calcium attenuate bone loss with antiretroviral therapy initiation: a randomized trial. Annals of Internal Medicine. 2015 Jun 16;162(12):815-24.

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Dominguez S et al.,

Efficacy and safety of tenofovir double‐dose in treatment‐experienced HIV‐infected patients: The tenoplus study. Journal of Medical Virology. 2007 Feb;79(2):105-10.

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Molina JM et al.,

Efficacy, safety, and effect on sexual behaviour of on-demand pre-exposure prophylaxis for HIV in men who have sex with men: an observational cohort study. The Lancet HIV. 2017 Sep 1;4(9):e402-10.

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Chow EP et al.,

Antiseptic mouthwash against pharyngeal Neisseria gonorrhoeae: a randomised controlled trial and an in vitro study. Sexually transmitted infections. 2017 Mar 1;93(2):88-93.

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Clement ME et al.,

Long-acting injectable cabotegravir for the prevention of HIV infection. Current Opinion in HIV and AIDS. 2020 Jan;15(1):19.

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Landovitz RJ et al.,

Cabotegravir for HIV prevention in cisgender men and transgender women. New England Journal of Medicine. 2021 Aug 12;385(7):595-608.

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Marzinke MA et al.,

Characterization of HIV infection in cisgender men and transgender women who have sex with men receiving injectable cabotegravir for HIV prevention: HPTN 083. The Journal of Infectious Diseases. 2021;20:1-2.

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Question-and-Answer Session