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2020 HIV Treatment Update: What’s New & What’s Coming Soon?

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2020 HIV Treatment Update:What's New & What's Coming Soon?
Brian R. Wood, MD
Associate Professor of Medicine
Division of Allergy and Infectious DiseasesUniversity of Washington, Seattle, WA
November 17, 2020
Thank you Dr. Jehan Budak, Dr. David Hachey, and Dr. David Spach for slide contributions.

No financial disclosures or conflicts of interest.Will be discussing investigational antiretrovirals.

Outline
Initial ART recommendations and ARV safety during conception and pregnancy
Optimizing ART, particularly considering weight change, metabolic syndrome, and cardiovascular risk
Newest antiretrovirals for salvage therapy

Resources
National HIV Curriculum: http://hiv.uw.edu
HHS Guidelines: https://clinicalinfo.hiv.gov/en/guidelines
IAS-USA Guidelines: https://jamanetwork.com/journals/jama/fullarticle/2771873

Case: Starting ART
30-year-old Latina woman referred after new HIV diagnosis
CD4 count 447 cells/mm3; HIV RNA 13,700 copies/mL; genotype pending
Presents with her male partner; they use condoms sometimes; his HIV screen is negative
She prefers not to start other contraception; hopes to have a baby within the next couple of years
Which ART regimen would you recommend for her?

POLL
Which ART regimen would you recommend for her? (insurance will not cover bictegravir/FTC/TAF)
Dolutegravir + FTC/TAF
Dolutegravir + FTC/TDF
Dolutegravir/ABC/3TC (assuming HLA-B5701 neg)
Dolutegravir/3TC
Raltegravir + FTC/TAF
Raltegravir + FTC/TDF

HIV Treatment as Prevention (TasP) and "U=U"Integration into Clinical Practice
HHS Adult and Adolescent Treatment Guidelines: https://clinicalinfo.hiv.gov/en/guidelines
Key message: consistent viral load <200 copies/mL prevents transmission of HIV to sexual partners
Inform persons with HIV about TasP/U=U, importance of ART adherence, and risk of transmission during periods off ART
Persons starting ART should use another form of prevention for >6 months and until HIV RNA <200 copies/mL

ART for Treatment-Nave IndividualsWhen to Start
Start immediately or as soon as possible in order to:- Increase the uptake of ART- Decrease time to virologic suppression- Reduce the risk of HIV transmission- Improve the rate of virologic suppression
Panel supports same-day start "when possible"
Emphasis on immediate ART for acute or early infection
HHS Adult and Adolescent Treatment Guidelines: https://clinicalinfo.hiv.gov/en/guidelines

ART for Treatment-Nave IndividualsWhat to Start
DHHS (Dec. 2019)1
Recommended for Most People With HIV
Bictegravir/FTC/TAF
Dolutegravir/ABC/3TC (if B*5701 neg)
Dolutegravir + FTC/TAF or FTC/TDF
Raltegravir + FTC/TAF or FTC/TDF
Dolutegravir/3TC (if HIV RNA <500k, no HBV, have baseline genotype results)
IAS-USA (Oct. 2020)2
Recommended for Most People with HIV
Bictegravir/FTC/TAF
Dolutegravir/ABC/3TC (if B*5701 neg)
Dolutegravir + FTC/TAFDolutegravir + FTC/TDF
Dolutegravir/3TC (not for rapid start; option if HIV RNA <500k, no HBV, CD4 >200)
Abbreviations:
ABC abacavir, 3TC lamivudine, FTC emtricitabine, TDF tenofovir disoproxil fumarate, TAF tenofovir alafenamide

Sources:
1. DHHS: clinicalinfo.hiv.gov/en/guidelines.
2. IAS-USA: https://jamanetwork.com/journals/jama/fullarticle/2771873
**DTG/3TC initial ART: see GEMINI results, updated to 144 weeks at Glasgow conference (comparison to TDF)
**IAS-USA Guidelines: Updated Oct 14, 2020
9

How do you choose TDF vs TAF for adults?(My opinions mixed in here)
Strong indications for TAF
Creatinine clearance <60 mL/min
Osteopenia or osteoporosis
Moderate indications for TAF
Risk factors for renal disease or osteopenia/osteoporosis
Age >50 (due to higher risk of TDF-induced renal toxicity)
Difficulty swallowing pills
Moderate indications for TDF
Post-exposure prophylaxis (PEP)
Trying to conceive or first trimester of pregnancy
Weak indications for TDF
Elevated BMI, metabolic syndrome, dyslipidemia

-- Side effect differences most significant with booster

Dolutegravir & Neural Tube Defects: Update

Tsepamo StudyBackground
1 - Zash. NEJM. 2018; 79:979. 2 - Zash. IAS 2019. Abstr MOAX0105LB
Birth-outcomes observational surveillance study in Botswana
Started in 2014 to evaluate neural tube defects (NTDs) associated with ART exposure at conception
In infants born to women who started dolutegravir (DTG) prior to conception, increased prevalence of NTDs observed
May 2018: 4/426 (rate: DTG 0.94% vs 0.12% non-DTG ART)1
April 2019: 5/1683 (rate: DTG 0.30%)2

IAS July 2018: 4/596 (0.67%)

Tsepamo StudyLatest Update: Data Through April 2020
Zash R et al. AIDS 2020. Abstract OAXLB0102.
NTD Outcome by Analysis, % (95% CI)
Conception
Pregnancy
HIV Negative
DTG
Non-DTG
EFV
DTG
Results as of March 2019
n =1683
n = 14,792
n = 7959
n = 3840
n = 89,372
NTD prevalence
0.30
(0.13-0.69)
0.10
(0.06-0.17)
0.04
(0.01-0.11)
0.03
(0-0.15)
0.08
(0.06-0.10)
Prevalence difference
Ref
0.20
(0.01-0.59)
0.26
(0.07-0.66)
0.27
(0.06-0.67)
0.22
(0.05-0.62)
Results as of April 2020
n = 3591
n = 19,361
n = 10,958
n = 4581
n = 119,630
NTD prevalence
0.19
(0.09-0.40)
0.11
(0.07-0.17)
0.07
(0.03-0.17)
0.04
(0.01-0.16)
0.07
(0.06-0.09)
Prevalence difference
Ref
0.09
(-0.03-0.30)
0.12
(0-0.32)
0.15
(0-0.36)
0.12
(0.01-0.32)

Tsepamo StudySummary
Zash R et al. AIDS 2020. Abstract OAXLB0102.
Take-Home Points: reassuring that DTG use at conception not higher risk than other ARV's; engage in shared-decision making and prioritize folate supplementation pre-conception

Perinatal GuidelinesLast updated April 2020
Perinatal Guidelines: https://clinicalinfo.hiv.gov/en/guidelines
Dolutegravir (DTG): - Preferredfor pregnant women, irrespective of trimester- Alternativefor women who are trying to conceive*
Tenofovir alafenamide (TAF): - Insufficient data**

*Not yet updated to incorporate most recent Tsepamo data

**Not yet updated to reflect IMPAACT 2010 (VESTED) data: TAF safe and potentially preferred over TDF when started after 14 weeks gestation (Chinula L et al, CROI 2020)
Preferred in pregnancy: RAL, ATV/r, DRV/r, TDF, ABC, 3TC/FTC

Case: Switching ART
52-year-old Black/African American man
Diagnosed with HIV in 2010; started efavirenz/TDF/FTC
Switched to dolutegravir + FTC/TAF in 2016
Robust CD4 count; routinely suppressed viral loads
Comorbidities: depression, chronic pain, HTN, type 2 DM (A1C's 7-9), OSA, BMI 34.5, GERD (takes famotidine)
Excellent adherence; wishes to minimize pill burden
Would you recommend an ART change to reduce long-term cardiac or metabolic risks related to weight changes?

POLL
Would you recommend an ART change? (insurance will not cover bictegravir/FTC/TAF, dolutegravir/3TC, or dolutegravir/rilpivirine)
A) Yes, to raltegravir-HD + FTC/TAF
B) Yes, to dolutegravir + rilpivirine
C) Yes, to dolutegravir + 3TC
D) Yes, to dolutegravir + doravirine
E) Yes, to doravirine/3TC/TDF
F) No, hold course, wait for long-acting options
Not excited about ABC options due to CVD risk? Or TDF options due to renal risk?

New Language on Weight Gain with ARTIAS-USA Guidelines
IAS-USA Guidelines: https://jamanetwork.com/journals/jama/fullarticle/2771873
Initiation of ART often leads to weight gain; can lead to obesity among individuals with HIV who start treatment with a normal or elevated baseline weight
Risk factors for excess weight gain: low CD4, high viral load, Black race, female sex, INSTI (especially DTG/BIC), TAF
Clinical consequences and mechanisms unknown and data insufficient to change recommendations for initial ART; PWH should be counseled about potential for weight gain

From Sax:
Through 96 weeks, 48.6%, 36.6%, and 17.3% of participants had
at least 3%, 5%, and 10% weight increase from baseline, respectively.
Weight gain was not observed in all participants; 30.2% lost weight

DISCOVER: 1.2 kg excess weight with TAF vs TDF
HPTN 083: also about 1 kg difference, but mostly first 40 weeks and driven by weight LOSS with TDF
??Composition of weight gain, long-term metabolic consequences, REVERSABILITY?
Initial ART: weight gain with all regimens, but more pronounced with BIC or DTG and TAF (Sax CID 2019); female sex and black race; ADVANCE: slow EFV metabolizers gain less weight higher EFV levels suppresses weight gain off target mitochondrial effects?
Lake: switch from EFV to INSTI-based regimens in ACTG trials; most weight gain when switch EFV to DTG
Clinical consequences: metabolic syndrome, CVD risk, neurocognitive impairment, fatty liver

Weight Gain with ARTMy Interpretation
1. Sax et al. CID 2019. 2. Mallon P et al. OPERA Cohort. AIDS 2020 Conference.
Most PWH who start ART gain some weight over the subsequent 12-24 months; median 2.0 kg [IQR -0.9 to 5.9]1
Small proportion gain excess weight, which likely increases risk of diabetes and metabolic syndrome; predictors include HIV/ART factors and social determinants of health
Some PWH gain weight after switching to TAF or to an INSTI; mean with TDF to TAF: 2-3 kg (in first 9 months)2
From Sax:
Through 96 weeks, 48.6%, 36.6%, and 17.3% of participants had
at least 3%, 5%, and 10% weight increase from baseline, respectively.
Weight gain was not observed in all participants; 30.2% lost weight

Weight Gain with ARTMy Interpretation
1. Sax et al. CID 2019. 2. Griesel R et al. CID Sept 2020.3. McComsey G et al. ID Week 2020. 4. Cahn. HIV Glasgow 2020.
Mechanism: likely secondary to previously unrecognized appetite suppression with TDF and older anchor drugs
ACTG ART initiation data (see figure)1
ADVANCE: higher EFV levels less weight gain on EFV and greater change after switch to INSTI2
McComsey: switch TDF to TAF more likely to gain than ABC to TAF3
GEMINI: mean weight gain 3.7 kg withDTG/3TC, 2.4 kg with DTG + FTC/TDF4
GEMINI: at 144 weeks

IM CAB Every 2 Months vs Oral Daily FTC/TDF for HIV PrEPHPTN 083 Pre-Exposure Prophylaxis Results
Annualized weight change
Source: Landovitz R et al. AIDS2020 Abstract OAXLB01.
Overall
Weeks 0-40
Weeks 40-105
P < 0.001
P < 0.001
P = 0.93
DISCOVER: 1.2 kg difference between TAF and TDF at 96 weeks
***Previously showed CAB did not lead to more weight gain than placebo so issue isn't CAB (INSTI), its TDF

Switch to DTG/3TC vs Continued TAF-Based 3-Drug ARTTANGO

Switch to DTG/3TC vs Continued TAF-Based 3-Drug ARTTANGO: Background
Source: van Wyk J, et al. Clin Infect Dis, Jan. 2020
Study Design: TANGO
Background: - Ongoing, phase 3, randomized, open label, multicenter, non-inferiority trial comparing switching to 2-drug DTG-3TC versus remaining on 3- or 4-drug TAF-based regimen
Enrollment Criteria:- Age 18 years- HIV RNA <50 copies/mL for >6 months - Taking 3- or 4-drug TAF-based ART- TDF to TAF switch allowed if 3 months before screening- No HBV or need for HCV treatment- No prior virologic failure- No prior NRTI or INSTI resistance
Switch Regimen
Dolutegravir/3TCn = 369
Maintain Regimen
TAF-Based Regimenn = 372
Primary endpoint: virologic response at 48 weeks by FDA snapshot

Switch to DTG/3TC vs Continued TAF-Based 3-Drug ARTTANGO: Baseline Characteristics
Source: van Wyk J, et al. Clin Infect Dis, Jan. 2020
Source: Cahn P et al. Lancet.2019;393(10167):143-155
Characteristic
DTG/3TC(n = 369)
TAF-Based ART(n = 372)
Age, years, median (range)
40 (20-74)
39 (18-73)
Female, n (%)
25 (7)
33 (9)
White, n (%)
297 (81)
289 (78)
African American/African, n (%)
50 (14)
58 (16)
CD4 cell count <500, n (%)
98 (27)
74 (20)
CD4 cell count 500, n (%)
271 (73)
298 (80)
Months on ART, median (range)
33.8 (7.1-201.2)
35.1 (7.0-160.8)
Baseline third agent class
INSTI (mostly ELV/cobi)
289 (78)
296 (80)
NNRTI (mostly RPV)
51 (14)
48 (13)
Boosted PI (mostly DRV)
29 (8)
28 (8)

Switch to DTG/3TC vs Continued TAF-Based 3-Drug ARTTANGO: Results
Week 48 Virologic Response (Intention-to-Treat Analysis)
Source: van Wyk J, et al. Clin Infect Dis, Jan. 2020
Confirmed withdrawal for virologic failure: 0 in DTG/3TC arm, 1 in TAF-based ART arm
No new resistance mutations occurred
4 with baseline M184V/I in DTG/3TC arm (by proviral genotype) suppressed at week 48
***96-week data presented at Glasgow

Source: van Wyk J, et al. AIDS 2020. Abstract OAB0606.
Weight change not significantly different: +0.81 kg with DTG/3TC vs +0.76 kg with continued TAF-based ART
TC, LDL, TG, & TC:HDL ratio improved in the DTG/3TC group & worsened in the comparator group
Risk of insulin resistance significantly lower in DTG/3TC
Improvements in lipids and insulin resistance driven by switch off a booster (EVG/cobi or boosted PI)
Switch to DTG/3TC vs Continued TAF-Based 3-Drug ARTTANGO: Metabolic Parameter Changes
**No difference in proximal tubulopathy outcomes (not showing here)
**No difference in proportion who developed metabolic syndrome

An AE of increased weight was reported for 3 (0.8%) participants in the DTG/3TC group and 6 (1.6%) in the TAF-based regimen group (regimens included cobicistat-boosted elvitegravir
[n = 2], RPV [n = 2], DTG [n = 1], and raltegravir [n = 1]). All increased weight AEs were grade 1/2. The adjusted mean weight increase from baseline to week 48 was 0.8 kg in both groups
(P = .863), and the adjusted mean increase in BMI was 0.25 kg/m2 in the DTG/3TC group and 0.26 kg/m2 in the TAF-based regimengroup (P = .932). There was a mean 9.7% decrease in adjusted geometric mean HOMA-IR in those who switched to DTG/3TC (baseline median HOMA-IR, 2.80) and a mean 4.5% increase in those who remained on a TAF-based regimen (baseline median HOMA-IR, 2.60; Figure 4), with a statistically significant difference between groups (0.864; P = .001). At baseline, 69% and 68%
of participants in the DTG/3TC and TAF-based regimen groups,
respectively, had HOMA-IR 2. At week 48, 65% of participants
in the DTG/3TC group and 74% in the TAF-based regimen
group had insulin resistance defined as HOMA-IR 2 (odds
ratio, 0.59; 95% CI, .40 to .87; P = .008; Supplementary Table 1).
Effects on inflammation biomarkers were small and inconclusive,
with significant differences observed in differing directions
for DTG/3TC and TAF-based regimens (Table 3). Changes in
renal biomarkers were minimal and similar between treatment
groups (Figure 5).
Mean baseline values were similar in the DTG/3TC and TAFbased
regimen groups for total cholesterol (5.0 mmol/L and
4.9 mmol/L, respectively), high-density lipoprotein (HDL) cholesterol
(1.4 mmol/L and 1.4 mmol/L, respectively), low-density
lipoprotein (LDL) cholesterol (2.9 mmol/L and 2.9 mmol/L, respectively),
triglycerides (1.6 mmol/L and 1.5 mmol/L, respectively),
and total cholesterol to HDL cholesterol ratio (3.9 and
3.9, respectively). Greater decreases from baseline were observed
with DTG/3TC vs TAF-based regimen for percentage changes in
total cholesterol, LDL cholesterol, and triglycerides (all P < .001)
and total cholesterol to HDL cholesterol ratio (P = .017; Figure 6).
HDL cholesterol decreased from baseline in the DTG/3TC group
and increased from baseline in the TAF-based regimen group;
however, the difference was not statistically significant (P = .059).

Key findings of the study are that at week 48:
Weight changes were not significantly different in the two groups: +0.81 kg after switch to DTG/3TC vs +0.76 kg with continued TAF-based ART
Total and low-density lipoprotein (LDL) cholesterol, triglycerides, and total cholesterol (TC)/high-density lipoprotein (HDL) ratio values improved in the DTG/3TC group (-4.5%, -5.5%, -11.2%, -3.3% respectively), while they worsened in the comparator group (2.3%, 2.2%, 6.0%, 0.5%). These differences were statistically significant.
Fasting glucose and HbA1c were not significantly different in the two groups, but fasting insulin was lower in the DTG/3TC switch group, as was the risk of insulin resistance (adjusted OR: 0.59;P= .008).
Metabolic syndrome: there was no significant difference in the proportions of subjects who developed metabolic syndrome
Improvements in lipid parameters and in insulin resistance were greater in subjects that switched from TAF-containing boosted regimens (EVG/c or boosted PIs) to DTG/3TC.

Also from AIDS 2020: Weight gain significantly greater if had only taken TAF for <1 year compared to >1 year

How about a switch to DOR/3TC/TDF?

Review of Doravirine (DOR)
Most recently approved NNRTI
Once-daily dosing with no food requirement
Fewer drug-drug interactions than previous NNRTI's
Better lipid effects compared to some previous NNRTI's
In vitro activity against isolates with some common NNRTI mutations (K103N, Y181C, K103N/Y181C, G190A, E138K)

Switch to DOR-TDF-3TC vs. Continued Baseline RegimenDRIVE SHIFT: Design
Source: Johnson M, et al. J Acquir Immun Defic Syndr. 2019;81:463-72.
Immediate Switch
DOR-TDF-3TC(n = 447)
Delayed Switch
Baseline Regimen to Week 24, then DOR-TDF-3TC
(n = 223)
1x
2x
DRIVE SHIFT: Study Design
Background: Open-label, active-controlled, non-inferiority trial that enrolled adults with suppressed HIV RNA on 2 NRTIs plus [a boosted PI, boosted elvitegravir, or an NNRTI], then randomized (2:1) to switch immediately to once-daily, single-tablet doravirine-tenofovir-DF-lamivudine (DOR/3TC/TDF) or continue baseline regimen until 24 weeks then switch.
Inclusion Criteria- Age >18 years- Suppressed HIV RNA 6 months- No history of virologic failure- Creatinine clearance >50 mL/min
Baseline Regimen- 2 NRTIs + boosted PI or EVG/cobi or NNRTI (*70% boosted PI, 25% NNRTI, 75% TDF)
**Very few switching from ELV (5%)
**NNRTI = mostly EFV

Switch to DOR-TDF-3TC vs. Continued Baseline RegimenDRIVE SHIFT: Results
Week 48 DOR-TDF-3TC vs Week 24 Baseline Regimen (FDA snapshot)
Source: Johnson M, et al. J Acquir Immun Defic Syndr. 2019;81:463-72.

Switch to DOR-TDF-3TC vs. Continued Baseline RegimenDRIVE SHIFT: Results
Change in Fasting Lipids in Participants Taking a Boosted PI at Baseline
Source: Johnson M, et al. J Acquir Immun Defic Syndr. 2019;81:463-72.

What Data Would Help Inform These Decisions?
What's Missing?
DTG/RPV compared to TAF-based 3-drug ART
Switch to DTG/3TC vs continue DTG + 2 NRTI's
Comparisons of DOR vs INSTI's
Switch to DTG + DOR

What's Coming?
ACTG 5391: enroll individuals who have gained weight on a TAF-containing INSTI regimen (RAL, BIC, or DTG); randomize to switch to DOR + TDF/FTC, switch to DOR + TAF/FTC, or continue current regimen
Missing overall: DOR vs INSTI comparisons
There is a switch study to DTG + boosted DRV (DUALIS) published, but typically want to avoid boosted PI

***There is a prospective study ongoing of switch to DOR/3TC/TDF in individuals who gained weight on an INSTI
Inclusion: 48 weeks INSTI+TAF/FTC (or TAF/3TC) dosing prior to study entry. BMI 27.5 kg/m2 with a >10% weight gain in the 1-3 years after initiating or switching to INSTI-based ART

Or, Let's Wait for Long-Acting IM Cabotegravir + Rilpivirine
**APPROVED IN CANADA in MARCH 2020; resubmitted to FDA in Summer 2020; likely approval in early 2021; mentioned in in new IAS-USA guidelines

Phase 2 Trials in Treatment Nave- LATTE: Oral CAB-RPV daily versus EFV plus 2 NRTI's- LATTE-2: IM CAB-RPV q1 or 2 months vs. oral CAB + ABC-3TC
Phase 3 Trials in Treatment Nave- FLAIR: IM CAB-RPV every month versus oral DTG-ABC-3TC
Phase 3 Trials in Treatment Experienced- ATLAS: Switch to monthly IM CAB-RPV or continue 3-drug ART- ATLAS-2M: switch to IM CAB-RPV every one or two months- LATITUDE: IM CAB-RPV for persons with detectable HIV RNA

Summary of Key StudiesCabotegravir-Rilpivirine
LATTE-2: 5-year data presented, rolled over to POLAR study (dosing every 2 months)

Long-Acting IM Cabotegravir and Rilpivirine for HIV MaintenanceATLAS Study: Design
Source: Swindells S, et al. N Engl J Med. 2020;382:1112-23.
Study Design:
Background: Phase 3, randomized, open-label trial assessing IM CAB-RPV after oral induction for adults taking 3-drug oral ART
Inclusion Criteria- Age 18 years- Taking an INSTI, NNRTI, boosted PI, or unboosted atazanavir, plus 2 NRTI's- Stable regimen & HIV RNA <50 copies/mL for 6 months- No history of virologic failure- No INSTI or NNRTI resistance (K103N allowed)- No chronic hepatitis B
IM CAB + RPV every 4 weeks(n = 308)
Continue 3-drug oral ART(n = 308)
Lead-In
Maintenance
4
Week
Daily oral CAB + RPV
48
Week

Long-Acting IM Cabotegravir and Rilpivirine for HIV MaintenanceATLAS Study: Baseline Characteristics
Source: Swindells S, et al. N Engl J Med. 2020;382:1112-23.
ATLAS: Baseline Characteristics
Characteristic
IM CAB + RPV(n = 308)
Oral ART(n = 308)
Overall (n=616)
Age, years, median
40
43
42
Female, n, %
99 (32)
104 (34)
203 (33)
White, n, %
214 (69)
207 (67)
421 (68)
Black, n, %
62 (20)
77 (25)
139 (23)
Median body-mass index
26
26
26
CD4 count <350 cells/mm3, n, %
23 (7)
27 (9)
50 (8)
Time since first ART (months), median, range
52 (7-222)
52 (7-257)
52 (7-257)
Third class agent, n, %
6
6
6
NNRTI (mostly EFV)
155 (50)
155 (50)
310 (50)
INSTI (mostly ELV/cobi)
102 (33)
99 (32)
201 (33)
PI
51 (17)
54 (18)
105 (17)
**Gotta dig into the supplemental material to see baseline regimens
**Only 2-3 people in each arm taking DTG
**Most common NRTI's? Mostly TDF, especially with EFV

Long-Acting IM Cabotegravir and Rilpivirine for HIV MaintenanceATLAS Study: Results
Weeks 48: Virologic Response by FDA Snapshot Analysis
Source: Swindells S, et al. N Engl J Med. 2020;382:1112-23.
30/33
HIV RNA > 50 copies/mL at 48 weeks: 1.6 % CAB-RPV, 1.0% 3-drug oral ART

Long-Acting IM Cabotegravir and Rilpivirine for HIV MaintenanceATLAS Study: Adverse Events
Source: Swindells S, et al. N Engl J Med. 2020;382:1112-23.
Injection Site Reactions (ISRs)
Reactions
Baseline N = 308
Participants who received injections, n
303
Any reaction, n (%)
250 (81)
Pain, n (%)
231 (75)
Grade 3 pain, n, (%)
10 (3)
Pain leading to withdrawal
4 (1)
Nodule, n (%)
37 (12)
Induration, n (%)
30 (10)
Swelling, n (%)
23 (7)
Median duration of reaction, days
3
The majority of ISRs (99%) were grade 1-2; 88% resolved within 7 days.
At week 48, median weight gains were 1.8 kg (IQR, 0.3 to 4.9) in the long-actingART group and 0.3 kg (IQR, 1.6 to 2.5) in the oral ART group.

Reflections on Long-Acting CAB-RPV
See also: Currier J. NEJM. March 2020;382(23)
Excellent option for carefully selected individuals
No resistance, likely to adhere to regular injections, no hep B
Struggling with pill fatigue or stigma; care transitions
Many operational & clinical questions
Burden on clinic staff
Every 1 vs 2 month dosing
Optimal oral lead-in, bridge for missed doses, oral tail
Role for persons with imperfect adherence/detectable VL
Injection site reaction fatigue over time
Metabolic/weight gain differences over standard oral ART
Costs/access

**Review ATLAS-2M; Review Cabenuva package insert from Canada (and oral cab, called Vocabria)

And of course ? Around timing of FDA approval and every 1 or 2 month dosing????
In December FDA rejected; no need for clinical data, but based on concerns re "chemistry manufacturing and controls"
Health Canada jointly approved orally administeredVocabria (cabotegravir) to be used as a short-term addition to Cabenuva.
At least in Canada, comes as 2 separate monthly injections (CAB + RPV); approved for virologically suppressed as maintenance

ATLAS 2M: CROI 2020

1045 participants were randomized and treated with CAB+RPV LA Q8W (n=522) or Q4W (n=523); 27% were female, 73% were white. Median age was 42 years (range 1983); 63% were nave to CAB+RPV LA while 37% transitioned from Q4W CAB+RPV LA in ATLAS. CAB+RPV LA Q8W was noninferior to Q4W dosing in both the primary (1.7% vs 1.0%) and secondary analysis (94.3% vs 93.5%; see Table). There were 8 and 2 confirmed virologic failures (CVFs; 2 sequential measures 200 c/mL) on Q8W and Q4W dosing, respectively; 5 and 0 CVFs, respectively, had archived resistance-associated mutations (RAMs) to RPV (E138A, Y188L, H221Y, Y181C) either alone (n=4) or with a CAB RAM (G140R, n=1) in baseline Peripheral blood mononuclear cells (PBMCs). On-treatment RAMs to RPV (K101E, E138K, M230L), CAB (N155H, Q148R, E138K), or both not present in baseline PBMCs were found in 5/8 Q8W CVFs and both Q4W CVFs. The safety profile was similar for Q4W and Q8W dosing (Table). Injection site reactions (ISRs) were mostly mild or moderate (98% overall) with a median duration of 3 days. Discontinuation for an adverse event occurred in 2% of patients (Q8W, n=12; Q4W, n=13), with 5 (1%) in each group due to ISRs. There was one death (Q8W; sepsis). Of those treated Q8W in ATLAS-2M after 48 weeks of Q4W dosing in ATLAS, 93% (115/124) expressed a preference for Q8W dosing.

Recommended Cabenuva Dosing ScheduleFrom Canadian Package Insert
gphandlahdpffmccakmbngmbjnjiiahp/https://viivhealthcare.com/content/dam/cf-viiv/viiv-healthcare/en_CA/cab...

Or, We Could Wait for Oral Islatravir plus Doravirine

What is Islatravir (ISL)?
Source: McComsey G, et al. CROI 2020. Abstract 686.
NRTTI: nucleoside reverse transcriptase translocation inhibitor

Potential Advantages of Islatravir (ISL)
Source: McComsey G, et al. CROI 2020. Abstract 686.
Active against isolates with pre-existing NRTI resistance
Potent viral load reduction plus high barrier to resistance
Inhibitory quotient achieved with low doses
Long intracellular half-life (190 hours with oral dosing)
Potential for once-daily, once-weekly, or less frequent oral dosing; much less frequent for other formulations

24
Oral ISL + DOR Dual ART Maintenance vs DOR/3TC/FTCDRIVE2SIMPLIFY: Background
Source: McComsey G, et al. CROI 2020. Abstract 686.
Study Design: DRIVE2SIMPLIFY
Background: - International, randomized, double-blind phase IIb trial
Enrollment Criteria:- Treatment-nave adults- HIV RNA >1,000 copies/mL- CD4 T-cell count >200 cells/mL- No ARV drug resistance- No active HBV or HCV
Primary Endpoint:- HIV RNA at 24 & 48 weeks; adverse events
ISL* + DOR + 3TCn = 90
DOR/3TC/TDFn = 31
*ISL dose: 0.25 mg, 0.75 mg, or 2.25 mg daily

Current analysis: weight; BMI; hip and spine BMD, peripheral & trunk fat by DXA; fasting plasma glucose; and lipid profile at 48 weeks
ISL + DOR
48
144
Weeks
ISL* + DOR

Oral ISL + DOR Dual ART Maintenance vs DOR/3TC/FTCDRIVE2SIMPLIFY: Results
Source: McComsey G, et al. CROI 2020. Abstract 686.
Change in weight & BMI similar in ISL + DOR groups and DOR/3TC/TDF group, and consistent with average weight gain in general population (0.5-1.0 kg/year)
ISL + DOR regimens had lower impact on hip BMD than DOR/3TC/TDF; spine BMD changes similar
Changes in glucose and fasting lipids modest and similar
Overall, minimal effects on body composition and metabolic parameters supports phase 3 trials of ISL + DOR
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Limitations: short follow-up, no TAF or INSTI comparison
**96-week efficacy data presented at Glasgow

Newest Options for Salvage ART

Case: New Drug for Salvage ART
57-year-old Caucasian man with 30-year history of HIV, complicated by neuropathy, lipodystrophy, chronic diarrhea
Chronic reduced renal function; estimated CrCl 45 mL/min
Significant NRTI, NNRTI, and INSTI resistance
Tropism assay: dual/mixed
Meds: atorvastatin, gabapentin, omeprazole, duloxetine
Would fostemsavir (FTR) be an option for this individual?

Fostemsavir (Rukobia)Attachment Inhibitor
CD4
HIV
CD4 binding site
CD4
CCR5
CCR5
Temsavir
HIV
Intracellular Space
Host Cell
Binds near CD4 binding site and prevents gp120 conformational change required for attachment
gp120
gp120
Attachment Inhibitor: The early interaction of HIV and the host cell involves binding of the host CD4 receptor and the binding site of the HIV gp120 envelope protein. The attachment inhibitorfostemsaviris an oral prodrug that is hydrolyzed to the active form temsavir, which binds to the HIV gp120 envelope adjacent to the gp120-CD4 binding site.[19,20]The binding of temsavir prevents the gp120 conformational change required for normal attachment to the CD4 receptor (Figure 5).[19]

Postattachment Inhibitor: The early interaction of HIV and the host cell involves binding of the host CD4 receptor and the HIV gp120 envelope. The initial attachment occurs with the domain 1 region of the host CD4 receptor and the HIV gp120 binding site. The humanized monoclonal antibodyibalizumabbinds to the domain 2 region of the host CD4 receptor and through steric hindrance it prevents the normal structural shifts that occur in gp120 that result in gp120-coreceptor binding (Figure 6); the net effect ofibalizumabis prevention of viral entry.[21,22]Ibalizumabdoes not block the initial attachment of CD4 domain 1 and HIV gp120. In addition,ibalizumabis not thought to interfere with CD4-mediated immune function since it does not interfere with CD4 binding of MCH class II molecules, which occurs at the CD4 domain 1 region

CCR5 Receptor Antagonists: The appropriate use of CCR5 antagonists depends on knowledge of the person's HIV subtype. There are three HIV subtypes related to the host coreceptor binding: R5 HIV (binds only to the CCR5 coreceptor; X4 HIV (binds only to the CXCR4 coreceptor); dual-tropic HIV (binds to either the CCR5 or CXCR4 coreceptor).[23,24]Individuals with a mixture of R5 HIV and X4 HIV have mixed-tropic HIV. The CCR5 antagonists bind to the CCR5 coreceptor, causing a conformational change in the coreceptor that prevents HIV gp120 from binding to the CCR5 coreceptor (Figure 7).[23,25]The CCR5 antagonists do not effectively block the entry of X4, dual tropic, or mixed tropic HIV. The drugmaravirocis the only FDA-approved CCR5 antagonist, and it is recommended for use in antiretroviral treatment-experienced individuals only if they have documented pure R5 HIV. Thus, prior to startingmaraviroc, an HIV coreceptor tropism assay must be performed; these assays reports provide information on the presence of R5, X4, and dual/mixed (the reports do not differentiate dual and mixed isolates).[23,25,26].
Figure 8.Mechanism of Action of Fusion Inhibitor
Fusion Inhibitor: In the normal fusion process, the HIV gp41 heptad repeat region 2 folds back on the heptad repeat region 1, in essence zipping up the gp41. This process pulls the HIV and host membranes together and results in the fusion of the viral and host membranes. The fusion inhibitorenfuvirtideis a 36-amino-acid synthetic peptide that corresponds to a 36-amino-acid segment in the HIV gp41 heptad repeat region 2 (Figure 8); theenfuvirtidepeptide binds to the heptad repeat region 1 of gp41, thus preventing the normal interaction and folding of the gp41 heptad repeat regions 1 and 2.[24,27,28]Enfuvirtideis the only FDA-approved fusion inhibitor. Unique among the antiretroviral agents, the route ofenfuvirtidedelivery is subcutaneous injection.

Ibalizumab (Trogarzo)Post-Attachment Inhibitor
Extracellular Space
CD4 Receptor
HIV

D2
IbalizumabBinds domain 2 of CD4 receptor; prevents normal structural shifts of gp120 that result in coreceptor binding
CCR5
CCR5
Intracellular Space
Host Cell
Postattachment Inhibitor: The early interaction of HIV and the host cell involves binding of the host CD4 receptor and the HIV gp120 envelope. The initial attachment occurs with the domain 1 region of the host CD4 receptor and the HIV gp120 binding site. The humanized monoclonal antibodyibalizumabbinds to the domain 2 region of the host CD4 receptor and through steric hindrance it prevents the normal structural shifts that occur in gp120 that result in gp120-coreceptor binding (Figure 6); the net effect ofibalizumabis prevention of viral entry.[21,22]Ibalizumabdoes not block the initial attachment of CD4 domain 1 and HIV gp120. In addition,ibalizumabis not thought to interfere with CD4-mediated immune function since it does not interfere with CD4 binding of MCH class II molecules, which occurs at the CD4 domain 1 region

Fostemsavir Take-Home Points
For heavily ART-experienced adults with few ARV options
Blocks attachment of the virus to CD4 at gp120
Works regardless of R5/X4 status
Oral tablet taken twice daily with or without food
Few drug interactions overall, but avoid CYP3A4 inducers
Rifampin contraindicated
Safe in renal impairment and hemodialysis; levels may increase with hepatic impairment
Answer: yes, FTR would be an option for the patient

Thank You!
Feel free to email questions or comments: [email protected]

Also in the PipelineNovel Delivery and Dosing Strategies
Weekly oral elsufavirine (NNRTI)
Implants: islatravir, TAF
Subcutaneous injections: lenacapavir (capsid inhibitor), albuvirtide (entry inhibitor)

New Language on Weight Gain with ARTHHS Guidelines
HHS Adult and Adolescent Treatment Guidelines: https://clinicalinfo.hiv.gov/en/guidelines
"Data from studies showing increased weight gain with particular ARV medications, including some INSTIs and TAF, and especially in certain patient populations (i.e., women, Black people, and Hispanic people)"
"There are now data suggesting greater weight gain with certain INSTI-based regimens and TAF than with other ARV drugs. The clinical significance of these findings is still unknown."
https://clinicalinfo.hiv.gov/en/guidelines

The More Distant Pipeline (Phase 2)
Elsufavirine: once-weekly oral NNRTI
GSK'232: oral maturation inhibitor
Lencapavir: subcutaneous capsid inhibitor

DUAL ART
MAINTENANCE ART STUDIES
Dolutegravir/rilpivirine1
SWORD (n=1,028, comparator: TDF-based 3-drug ART)
Dolutegravir/3TC2
TANGO (n=750, comparison: TAF-based 3-drug ART)
Dolutegravir + FTC3
SIMPL'HIV(n=188, comparison: TAF, TDF, ABC-based 3-drug ART)
Boosted darunavir + 3TC4
DUAL GESIDA (n=249, comparator: TDF-based 3-drug ART)
Boosted darunavir + dolutegravir5
DUALIS (n=263, comparison: TDF-based 3-drug ART)
Oral 2-Drug Maintenance ARTProspective RCT's
1. 148 Week Data: van Wyck, BHIVA, April 2019.
2. 48 Week Data: van Wyck, IAS, July 2019.
3. 48 Week Data: Sculier, EACS, Nov 2019.
4. 48 Week Data: Pulido, CID, 2017.
5. 48 Week Data: Spinner C, IAS 2019.
DTG/3TC for treatment-nave: GEMINI study, Lancet

Long-Acting IM Cabotegravir and Rilpivirine after Oral InductionFLAIR Study: Results
Source: Orkin C, et al. N Engl J Med. 2020;382:1124-35.
Participants in the IM CAB + RPV arm with viral rebound meeting protocol-defined criteria for genotype resistance testing
Sex, Country, HIV-1 Subtype, Viral Load (Baseline)
Baseline INSTI RAMs
Baseline NNRTI RAMs
Viral Load at Confirmed Virologic Failure
INSTI RAMs at Virologic Failure
F, Russia, A1, 54,000 copies/mL
L74I
None
456 copies/mL
L74I, Q148R
M, Russia, A1, 23,000 copies/mL
L74I
None
299 copies/mL
L74I, G140R
F, Russia, A1, 20,000 copies/mL
L74I
None
440 copies/mL
L74I, Q148R
There were also 3 virologic failures in the DTG-ABC/3TC arm; no new RAM's detectedAbbreviations: RAMs = resistance associated mutations

Switch to DTG/3TC vs Continued TAF-Based 3-Drug ARTTANGO: Results
Week 48 Changes in Markers of Proximal Tubulopathy (Urine Tests)
Source: van Wyk J, et al. Clin Infect Dis. 2020. Jan 6. [Epub ahead of print]

Oral ISL + DOR Dual ART Maintenance vs DOR/3TC/FTCDRIVE2SIMPLIFY: Results
Source: McComsey G, et al. CROI 2020. Abstract 686.
DRIVE2SIMPLIFY: Metabolic Results at 48 Weeks
Characteristic
Combined ISL + DOR Groups(n = 90)
DOR/3TC/TDF(n = 31)
Mean % change in weight
3.8
3.0
Mean % change in hip BMD
-1.1*
-3.5
Mean % change in spine BMD
-1.3
-2.2
Mean % change in peripheral fat
10.2
9.6
Mean % change in trunk fat
15.0
12.9
Mean change in fasting markers (mg/dL)
Glucose
2.3
-2.0
Total cholesterol
5.4
-6.5
HDL
4.3
0.8
LDL
-0.8
-4.7
Triglycerides
6.2
-10.9
*p <0.05
No significant difference in # who initiated lipid-lowering therapy at screening or during trial