Review from the 24th Conference on Retroviruses and Opportunistic Infections (CROI) – 2017

Review from the 24th Conference on
Retroviruses and Opportunistic Infections
(CROI) – 2017
Seattle, Washington
Charles Hicks, M.D.
Professor of Clinical Medicine
April 21, 2017

Speaker Disclosures – April 2017
Charles Hicks, MD
• Royalties: UpToDate, Inc.
• Consulting Fees: Gilead, ViiV, Merck, Janssen Virology
• IDMC: Medimmune (D5170C00002 Study)
• Other: Massachusetts Medical Society/NEJM: Associate
Editor and Contributor for Journal Watch-ID

33
Program Overview
• HIV epidemiology, testing, and engagement in care
• HIV prevention
• ART trials and new agents
• Cardiovascular and other complications

44
CDC:
Estimated New HIV Infections in the US (2008-2014)
Singh S, et al. 24th CROI. Seattle, 2017. Abstract 30.
0
10
20
30
40
50
NumberofCases(thousands)
Change in Estimated New HIV Infections/Year
(2008-2014)
2008 2009 2010 2011 2012 2013 2014
MSM*
(-0.7%)
PWID
(-13.8)
Persons Living
With Undiagnosed
HIV in 2014 (%)
Heterosexual
Contact
(-7.3%)
17%
16%
6%
Total
(-3.6%)
15%
*Among MSM, HIV incidence decreased among black and white MSM (-0.7% and -3.1%, respectively). In contrast,
HIV incidence increased among MSM Hispanics (2.4%) and 25-34 year olds (4.8%).
In 2014, 52% of young MSM with HIV were undiagnosed.

5
CDC National HIV Surveillance System (2014): Diagnosed HIV
Patients With Durable HIV RNA <200 Copies/mL
Crepaz N, et al. 24th CROI. Seattle, 2017. Abstract 31.
PLWDH: persons living with diagnosed HIV.
HIV diagnosed by year-end 2013 and alive in 2014 from 33 jurisdictions (n=630,965; ~70% of persons living with diagnosed HIV in US).
Durable viral suppression in 2014: all HIV RNA tests <200 copies/mL.
0
10
20
30
40
50
60
PLWDH With Durable Viral Suppression in 2014
PLWDH(%)
Male
49%
44%
40%
48%
56%
53%
Female
Sex
Black Hispanic
Race/Ethnicity
White MSM Male
IDU
Risk factor/sex
MSM
IDU
Male
Hetero
Female
IDU
Female
Hetero
13-24 25-34
Age Group (years)
35-44 45-54 ≥55
38%
48%
44%
41%
48%
33%
40%
45%
50%
53%

66
HOPS Cohort (1999-2015):
Trends in Syphilis Among HIV-Infected Persons
• HOPS cohort (n=6888)
– Male (78%), MSM (57%), heterosexual (36%), PWID (10%)
– Syphilis diagnoses (n=799 among 641 persons over a
median follow-up of 5.2 years)
• Factors associated with incident syphilis (adjusted OR)
– Age 18-30 (versus 31-40): 1.3 (P=0.003)
– Black (versus white): 1.6 (P<0.001)
– Calendar year (versus 1999)
• 2000-2004: 1.5 (P<0.001)
• 2005-2009: 2.1 (P<0.001)
• 2010-2015: 4.2 (P<0.001)
• Data underscore the need for ongoing syphilis testing
and comprehensive sexual risk reduction interventions
Novak R, et al. 24th CROI. Seattle, 2017. Abstract 864.
Incidence
Calendar year
1999/2009/2015 0.4/2.5/2.3
Age group (years)
18-30
31-40
41-50
≥51
3.2
1.9
1.5
0.8
Sex
Male/Female 2.2/0.4
Race/ethnicity
White
Black
Hispanic
1.7
2.2
1.3
Transmission risk
MSM
Heterosexual
Male
Female
2.6
1.0
0.4
Syphilis Incidence Rates
(per 100 person years)

77
CDC: HIV Integrase Genotypic Testing and
Resistance Data from 9 US Jurisdictions (2010-2014)
• Integrase sequences performed in persons
with HIV diagnosis (n=14,468)
• Integrase genotypic testing increased over
time
– More commonly performed among male, 20-
29 years of age, blacks, high population areas,
non-AIDS
• Prevalence of INSTI-associated resistance
mutations among all INSTI sequences:
0.4% (65/14,468)
– Most prevalent mutations: N155H (38%),
E92Q (29%), and G140S (25%)
• Prevalence of transmitted INSTI-resistant
mutations of those diagnosed with HIV in
the last 3 months: 0.04% (2/4631)
Hernandez AL, et al. 24th CROI. Seattle, 2017. Abstract 478.
Patients(%)
0
10
20
30
40
50
N155H
Prevalence of INSTI-Associated
Resistance Mutations Among
Patients With INSTI Resistance
E92Q G140S Q148H Y143R Q148R Y143C

88
Program Overview
• HIV prevention

9
King County, Washington (2014-2016):
STD Partner Services Program and PrEP Referrals
Katz DA, et al. 24th CROI. Seattle, 2017. Abstract 89.
STD Partner Services offered to HIV-negative MSM diagnosed with bacterial STDs and their partners (n=3936);
of whom 57% (n=549) received partner services, were at high risk for HIV, and were not on PrEP.
Disease Intervention Specialist
Attempt to provide partner services to all MSM with STIs
Assess HIV status and PrEP eligibility
• Early syphilis or rectal gonorrhea
• Use of methamphetamine or poppers
• Sex work
• HIV-partner with detectable HIV RNA
HIV-Negative MSM at High Risk
• Chlamydia or urethral/pharyngeal
gonorrhea without behavioral risk
HIV-Negative MSM at Lower Risk
Offer Referral to PrEP at
Public Health STD Clinic or
Community Providers
Offer Referral to Community
Providers for PrEP

1010
King County, Washington (2014-2016):
PrEP Referrals and Trends in PrEP Usage
• Trends in PrEP usage among MSM
with STDs (2014→2016)
– All STDs: 24%→45%
– Symptomatic STDs: 16%→40%
– Early syphilis/rectal gonorrhea:
21%→53%
– Other high risk: 30%→58%
– Lower risk: 15%→36%
• Significantly lower PrEP use among
Asian and black versus white MSM
(21% and 22% versus 40%; P<0.001)
• STD partner services represent an
opportunity to promote PrEP for MSM
at high risk for HIV
Katz DA, et al. 24th CROI. Seattle, 2017. Abstract 89.
0
10
20
30
40
50
60
70
PrEP Referral Outcomes Among MSM
With STD and Not on PrEP (n=549)
Percent
Offered
PrEP
Referral
Accepted
PrEP
Referral
Accepted
Clinic
Referral
Attended
PrEP
Assessment
Visit
62%
31%
23%
13%
21% of MSM Offered PrEP,
Attended 1st Visit

1111
EleMENt PrEP Study: Challenges in Translating PrEP
Interest into Uptake Among Young Black MSM
• Prospective, observational study on
substance use and HIV risk in Atlanta
– HIV-negative, young black MSM (16-29
years of age)
– Recruited from the community irrespective of
initial PrEP awareness or interest
– All were offered PrEP as part of standard HIV
prevention package
• Initiated PrEP: 34% of total cohort
• Reasons for discontinuing PrEP (n=11)
– Voluntary withdrawal (n=8)
– HIV seroconversion (n=3, none taking PrEP
at time of diagnosis)
• Annualized HIV seroconversion rate of
entire cohort: 5.3% (95% CI: 1.9, 11.6)
Rolle C-P, et al. 24th CROI. Seattle, 2017. Abstract 90.
Cohort
(%)
MSM eligible for PrEP enrollment (n=184)
Not interested in PrEP
Wanted to discuss PrEP at next visit
Interested in PrEP initiation
10
27
63
Among those interested in PrEP (n=116)
Have not yet attended 1st visit
Initiated PrEP
54
46
Among those who initiated PrEP (n=63)
Currently on PrEP
Discontinued
83
17
MSM Eligible for PrEP Enrollment

1212
Secondary Analysis of FAME-04: Impact of Vaginal Microbiota
on Genital Tissue and Plasma Levels of Tenofovir
• Phase 1, substudy of FAME-04 of healthy,
nonpregnant, seronegative women (n=41)
– Mean age: 28 years; white: 71%, no STIs
• Substudy design (7 days)
– Daily application of tenofovir (days 1 and 7
in clinic, days 2-6 in home)
– qPCR at baseline
– Cervical biopsy day 7 (2-hours post dose)
• Women having vaginal microbiota associated
with bacterial vaginosis had lower levels of
tenofovir (plasma and cervical tissue)
Hillier SL, et al. 24th CROI. Seattle, 2017. Abstract 86LB.
FAME: Film Antiretroviral Microbiota Evaluation.
qPCR performed for:
Lactobacillus crispatus, L. jensenii, L. gasseri, L. iners.
Gardnerella vaginalis.
Atopobium vaginae.
*Cervical tissue (tenofovir diphosphate); plasma (tenofovir).
Cervical
Tissue Plasma
G. vaginalis
After 6 doses
Cervical biopsy tissue
↓(P=0.032)
↓(P=0.019)
↓(P=0.051)
↓(P=0.001)
L. crispatus, L. jensenii,
and L. gasseri
After 6 doses
Cervical biopsy tissue
↑(P=0.003)
↓(P=0.025)
↑(P=0.021)
↓(P<0.001)
L. iners
After 6 doses ↔ ↔
Atopobium vaginae
Cervical biopsy tissue ↓(P=0.006) ↓(P=0.003)
Nugent score ↓(P=0.045) ↓(P=0.001)
Association of Microbiota and
Tenofovir Levels in Cervical
Tissue and Plasma
Tenofovir Levels*

13
Partners PrEP Substudy: Impact of Bacterial
Vaginosis on HIV Prevention With Daily Oral PrEP
Heffron R, et al. 24th CROI. Seattle, 2017. Abstract 85.
Double-Blind
Phase 3, Double-Blind Study
Kenya, Uganda
Serodiscordant, heterosexual
couples (n=4758)
(HIV-positive partner not yet
eligible for ART)
Normal liver, renal,
hematologic values/function
Randomization
1:1
Placebo (n=1584)
Tenofovir DF qd (n=1584)
Emtricitabine/Tenofovir DF qd (n=1579)
Follow for up to 36 months
Primary endpoint for substudy: incident HIV infection
among women with and without bacterial vaginosis
(Nugent score 7-10 versus 0-3)
Nugent score algorithm includes individual scores for:
Lactobacillus morphotypes.
Gardnerella/Bacteroides morphotypes.
Curved-gram variable rods.
Baseline characteristics of women in substudy (n=1470):
Median age: 33 years.
Randomized to PrEP: 67%.
Any sex acts without condom in prior month: 23%.
Nugent score:
0-3 (normal): 64%.
4-6 (intermediate): 12%.
7-10 (bacterial vaginosis): 24%.

14
Partners PrEP Substudy:
PrEP Efficacy by Presence of Bacterial Vaginosis
Heffron R, et al. 24th CROI. Seattle, 2017. Abstract 85.
HIVincidence(100person-years)
0
1
2
3
4
2.5
Normal
(Nugent 0-3)
73% Efficacy
(P=0.001)
No PrEP
PrEP
Intermediate
(Nugent 4-6)
Bacterial Vaginosis
(Nugent 7-10)
0.6
3.5
1.8
3.5
0.9
PrEP Was Protective Against HIV Acquisition for Each Category of Nugent Score
63% Efficacy
(P=0.2)
77% Efficacy
(P=0.04)
Differences in levels of HIV prevention efficacy were not statistically significant (P=0.9).

15
On-Demand Post-Exposure Prophylaxis With
Doxycycline for MSM
Molina J-M, et al. 24th CROI. Seattle, 2017. Abstract 91LB.
On Demand PEP Doxycycline 200 mg
(~24 hours after sex, up to 72 hours)
Open-Label Study
(n=232)
HIV-negative high-risk MSM
enrolled in the open-label
Ipergay extension study
No contraindication to
doxycycline
Randomization
1:1
No PEP
Visits: baseline and every 2 months
Serologic assays for HIV and syphilis
PCR assays for chlamydia and gonorrhea
Urine, anal, and throat samples collected
Baseline characteristics:
Median age: 38-39 years.
White: 95%.
History of PEP use in Ipergay: 19%.
Use of psychoactive drugs
(ecstasy, crack, cocaine, crystal, speed, GHB/GBL): 42%.
Circumcised: 21%.
Prior gonorrhea, chlamydia, syphilis infection: 16%.
Number of sexual acts in prior 4 weeks: 10.

16
Time to First STI With On-Demand PEP With
Doxycycline for MSM
0
0.1
0.2
0.3
0.4
0.5
Time to First STI (ITT)
CumulativeProbability
0 2 4 6 8 10
Months
No PEP
PEP
Median follow-up: 8.7 months
Incidence of STIs (n=73 with STI):
No PEP (n=45): 70/100 person-years.
PEP (n=28): 38/100 person-years.
HR: 0.53
(P=0.008)

17
Time to First Chlamydia and Syphilis Infection With
On-Demand PEP With Doxycycline for MSM
0
0.1
0.2
0.3
Time to First Chlamydia (ITT)
0 2 4 6 8 10
Months
No PEP
PEP
Incidence of chlamydia (n=28):
HR: 0.30
(P=0.003)
0
0.1
0.2
0.3
Time to First Syphilis (ITT)
0 2 4 6 8 10
Months
No PEP
PEP
Incidence of syphilis (n=13):
HR: 0.27
(P=0.04)

1818
Time to First Gonorrhea Infection With
• No effect on gonorrhea incidence
• Number of sites of gonorrhea
infection (PEP versus no PEP)
– Anus: 11 versus 19
– Throat: 15 versus 12
– Urine: 1 versus 7
0
0.1
0.2
0.3
Time to First Gonorrhea (ITT)
0 2 4 6 8 10
Months
No PEP
PEP
Incidence of gonorrhea (n=47):
HR: 0.83
(P=0.52)

1919
Conclusions:
• PEP reduced the overall incidence of bacterial STI by 47% in MSM on
PrEP (8.7 months of follow-up)
• No effect on gonorrhea, but strong reduction in chlamydia and syphilis
• No evidence of sexual risk compensation
• Analysis of antibiotic resistance is pending
• Long-term benefit of PEP is not yet known
• Antibiotic prophylaxis for STIs is still not recommended
• More research is needed

2020
Acute Infection With a Wild-Type HIV-1 Virus in a
PrEP User With High TDF Levels
• MSM 50 years of age at time of starting daily PrEP
– HIV negative prior to PrEP and 1, 3, and 6 months after starting PrEP
– Reported excellent adherence (adequate TDF-DP levels at 6 and 8 months after starting PrEP)
• During PrEP use
– STIs (2 episodes of rectal gonorrhea, 1 episode of rectal chlamydia)
– Anal sex partners: 38 to 70 per month
– Drug use during sex (amphetamine, cocaine, GHB/GBL, mephedrone, and ketamine)
• 8 months after PrEP start
– PrEP interrupted
• Fever and dysuria
• HIV Ab positive, HIV Ag and HIV RNA negative, no detectable HIV DNA
– HIV RNA detectable 3 weeks after PrEP interrupted (undetectable HIV RNA achieved with ART)
• No mutations detected (routine sequencing)
• Underscores the importance of regular HIV testing on PrEP and awareness of atypical
patterns of HIV seroconversion
Hoornenborg E, et al. 24th CROI. Seattle, 2017. Abstract 953.

2121
Program Overview
• HIV prevention

22
Studies 104 and 111:
E/C/F/TAF Versus E/C/F/TDF in Initial HIV Therapy
E/C/F/TAF qd (n=866)
(Elvitegravir/cobicistat/
emtricitabine/TAF)
E/C/F: elvitegravir/cobicistat/emtricitabine.
TAF: tenofovir alafenamide 10 mg; TDF: tenofovir DF 300 mg.
Non-inferiority margin: 12% (based on week-48 FDA snapshot analysis of percentage of patients with HIV RNA <50 copies/mL).
Male: 85%.
Black race/ethnicity: 26%.
Median HIV RNA: 4.5 log10 copies/mL.
Median CD4 count: 405 cells/µL.
Median eGFR: 114-117 mL/min.
E/C/F/TDF qd (n=867)
(Elvitegravir/cobicistat/
emtricitabine/tenofovir DF)
Phase 3
(2 trials combined)
Treatment-naive
HIV RNA >1000 copies/mL
eGFR >50 mL/min
No HBV or HCV coinfection
Week 0 144
Randomization
1:1
Arribas JR, et al. 24th CROI. Seattle, 2017. Abstract 453.
Arribas JR, et al. JAIDS. 2017;Mar 9. [Epub ahead of print].
Current
Analysis

Initial ART With E/C/F/TAF Superior to
E/C/F/TDF at Wk 144
 Efficacy similar across pt
subgroups, trending
toward or significantly
better with TAF in each
group
– By baseline HIV-1 RNA,
baseline CD4+ cell count,
adherence, age, sex,
race, region
 Virologic failure with
resistance by Wk 144:
1.4% in each arm
Arribas JR, et al. CROI 2017. Abstract 453. Sax PE, et al. Lancet.
2015;385:2606-2615.
0
20
60
40
80
100
48 96 144 48 96 144 48 96 144Wk:
Virologic
Success
Virologic
Failure
No Data
E/C/F/TAF (n = 866)
E/C/F/TDF (n = 867)
92908785 84
80
4 4 5 4 5 4 4 6
9 11 11
16
Pts(%)
Treatment Difference
Wk 48: 2.0% (95% CI: -0.7% to
4.7%)
Wk 144: 4.2% (95% CI: 0.6% to
7.8%; P = .02)
Slide credit: clinicaloptions.com

2424
Studies 104 and 111: Changes in Spine and Hip BMD
With E/C/F/TAF or E/C/F/TDF at Week 144
E/C/F: elvitegravir/cobicistat/emtricitabine.
TAF: tenofovir alafenamide; TDF: tenofovir DF.
Hip BMD
MeanChange(%)
-4
-3
-2
-1
0
1
2
-3.4
E/C/F/TAF (n=836)
E/C/F/TDF (n=848)
-0.8
P<0.001
Treatment Week
Spine BMD
MeanChange(%)
-4
-3
-2
-1
0
1
2
-3.0
E/C/F/TAF (n=845)
E/C/F/TDF (n=850)
-0.9
0 48 96 144
P<0.001
Treatment Week
0 48 96 144
Arribas JR, et al. 24th CROI. Seattle, 2017. Abstract 453.
Arribas JR, et al. JAIDS. 2017;Mar 9. [Epub ahead of print].

Initial ART With E/C/F/TAF vs E/C/F/TDF:
Wk 144 Safety Outcomes
 Rate of discontinuation for AEs
higher with TDF vs TAF regimen
– 3.3% vs 1.3% (P = .01)
 Spine and hip BMD loss greater
with TDF vs TAF regimen
– 6 discontinuations for bone AEs in
TDF arm vs 0 in TAF arm
 TC, LDL, and HDL increases
greater with TAF vs TDF regimen,
but no difference in TC:HDL ratio
– Rates of lipid-modifying therapy
initiation similar: 5.5% vs 5.8%
Renal Events
Leading to
Discontinuation, n
E/C/F/TAF
(n = 866)
E/C/F/TDF
(n = 867)
Proximal renal
tubulopathy
0 4
Cr elevation or
eGFR decrease
0 3
Renal failure 0 2
Nephropathy 0 1
Proteinuria 0 1
Bladder spasm 0 1
Total 0 12
Arribas JR, et al. CROI 2017. Abstract 453. Slide credit: clinicaloptions.com

Switch to EVG/COBI/FTC/TAF in
Virologically Suppressed Women
 WAVES: international, randomized, double-blind phase III trial comparing
EVG/COBI/FTC/TDF vs ATV/RTV + FTC/TDF in 575 treatment-naive
women[1]
 Women completing 48 wks ATV/RTV + FTC/TDF in WAVES rerandomized in
current trial[2]
 No treatment-emergent resistance in either treatment arm
 At Wk 48, pts receiving TAF had higher mean % increase in lumbar spine and
total hip BMD, improved renal safety markers, and greater lipid increases vs
TDF regimen, but no difference in TC:HDL ratio
1. Squires K, et al. Lancet HIV. 2016;3:e410-e420. 2. Hodder S, et al.
CROI 2017. Abstract 443.
Switch to EVG/COBI/FTC/TAF
(n = 159)
Continue ATV/RTV + FTC/TDF
(n = 53)
Virologically suppressed
women who completed 48
wks of ATV/RTV +
FTC/TDF in WAVES trial
(N = 212)
Wk 48 Wk 48 HIV-1 RNA < 50 c/mL
by FDA Snapshot
Difference:
7.5% (95%
CI: -1.2 to
19.4)
94%
87%
•

27
SWORD-1 and -2: Switch to Dolutegravir + Rilpivirine
in Patients on Stable ART
Llibre JM, et al. 24th CROI. Seattle, 2017. Abstract 44LB.
Dolutegravir +
Rilpivirine
(n=513)
Stable ART
(n=511)
Week 0 52 148
Randomization
1:1
48
Dolutegravir +
Rilpivirine
Late-Switch
Phase
Early-Switch
Phase
Continuation
Phase
Dolutegravir +
Rilpivirine
Primary
Endpoint
HIV RNA <50 copies/mL
(ITT-E snapshot)
2 Identical
Phase 3 Studies
(Open-Label)
On stable ART ≥6 months
(INSTI, NNRTI, or PI + 2 NRTIs)
for 12 months
HBV negative
Dolutegravir 50 mg qd + rilpivirine 25 mg qd.
Non-inferiority margins:
Individual studies: -10%.
Pooled data: -8%.
Median age: 43 years.
Male: 78%.
White: 80%.
Median CD4 count: 611-638 cells/mm3.
CD4 ≤500 cells/mm3: 31%.
ART 3rd agent PI/NNRTI/INI: 26%/54%/20%.
Baseline tenofovir DF use: 72%.
Duration of ART use: 51-53 months.

2828
SWORD-1 and -2: Pooled Outcomes at Week 48
After Switch to Dolutegravir + Rilpivirine
• Dolutegravir + rilpivirine was
non-inferior to stable ART for both
pooled data and in each individual
study
– Treatment difference
• SWORD-1: -0.6 (95% CI: -4.3, 3.0)
• SWORD-2: 0.2 (95% CI: -3.9, 4.2)
• No INSTI treatment-emergent
resistance in either arm
– Confirmed virologic withdrawal with
dolutegravir + rilpivirine (n=1 with
K101K/E, re-suppressed with
dolutegravir + rilpivirine)
Patients(%)
0
20
40
60
80
100 95%
Dolutegravir +
Rilpivirine
(n=513)
Stable ART
(n=511)
HIV RNA <50 Copies/mL
-0.2 (-3.0, 2.58)
95%

2929
SWORD-1 and -2: Safety Outcomes at Week 48
After Switch to Dolutegravir + Rilpivirine
• Safety of dolutegravir + rilpivirine
was consistent with their respective
full prescribing information
– Discontinuations due to adverse
events (overall: 4%, CNS-related: 2%)
• Switch to dolutegravir + rilpivirine
– Neutral effect on lipid profile
– Significant improvement on bone
turnover biomarkers
Dolutegravir +
Rilpivirine
(n=513)
Stable
ART
(n=511)
Adverse events (%)
Nasopharyngitis
Headache
Upper RTI
Diarrhea
Back pain
10
8
5
6
3
10
5
7
5
6
Lipid changes (mg/dL)
Total cholesterol
HDL-C
LDL-C
Triglycerides
<1
2
1
-12
<1
2
-<1
<1
Change in bone turnover
markers (µg/L)
Bone-specific alkaline
phosphatase
Osteocalcin
Procollagen 1 N-terminal
propeptide
-3*
-4.8*
-7.4*
0.9
-0.9
-0.6
Safety at Week 48
*P<0.001 versus stable ART (adjusted for baseline third agent,
age, sex, BMI, smoking status, and baseline biomarker level).

30
LAMIDOL Trial:
Dolutegravir + Lamivudine as Maintenance Therapy
Joly V, et al. 24th CROI. Seattle, 2017. Abstract 458.
Open-Label
(2 phases, 56 weeks)
Treatment-experienced
Stable ART
(HIV RNA <50 copies/mL for ≥2 years)
Nadir CD4 >200 cells/mm3
No major resistance mutations
No HBV
Dolutegravir
+ 2 NRTIs
*2 NRTIs: lamivudine or emtricitabine plus another NRTI.
Primary endpoint: proportion of patients with HIV RNA <50 copies/mL at week 56 (ie, 48 weeks on dual therapy).
Male: 86%.
Age: 45 years.
MSM: 70%.
Time on current ART: 4 years.
CD count: 743 cells/mm3.
Stable ART (3rd agent):
NNRTI: 56%.
PI: 23%.
INSTI (not dolutegravir): 21%.
Week 0 8 48 56
Phase 2 Entry
HIV RNA
<50 copies/mL
Dolutegravir
+ Lamivudine
Phase 1
(n=110)
Phase 2
(n=104)
Current
Analysis

3131
LAMIDOL Trial: Treatment Outcomes With
Dolutegravir + Lamivudine as Maintenance Therapy
• Similar proportion of patients
achieved HIV RNA <50 copies/mL
before and after switching to
dolutegravir + lamivudine
– Maintenance failure (n=3; virologic
failure, lost to follow-up, and
treatment modification)
• Blips, but not virologic failure,
during phase 2 that did not require
ART modification (n=2 with ≥1
value of HIV RNA >50 copies/mL)
• Maintenance therapy was
generally safe and well tolerated
Joly V, et al. 24th CROI. Seattle, 2017. Abstract 458.
Patients(%)
0
20
40
60
80
100 95%
Phase 1
(n=110)
Phase 2
Week 40
(n=104)
97%

DOMONO: Switch to DTG Monotherapy in
Virologically Suppressed Pts Not Sufficient
 Randomized comparison of switch to DTG 50 mg QD monotherapy
(immediate switch) vs continued baseline ART for 24 wks followed by
switch to DTG 50 mg QD monotherapy (delayed switch) in
virologically suppressed pts with no previous VF[2]
 At Wk 24, DTG monotherapy noninferior to continued baseline ART
for maintained HIV-1 RNA < 200 c/mL
– After 24 wks, all pts allowed to switch to DTG QD monotherapy
 Study d/c early because of high VF rate after 48 wks of DTG
monotherapy
– VF in 8/77 pts with DTG monotherapy vs 3/152 pts on combination ART in
concurrent nonrandomized control group (P = .03)
– Among 6 VF cases with resistance data in DTG monotherapy group,
3 developed INSTI resistance
Wijting I, et al. CROI 2017. Abstract 451LB. Slide credit: clinicaloptions.com

Emergent INSTI Resistance After Switch to
DTG Monotherapy
 International, multicenter retrospective study
evaluated virologically suppressed pts switched from
combination ART to DTG 50 mg QD monotherapy
– Pts with history of VF on INSTI and INSTI resistance
excluded
 11 of 122 pts switched to DTG monotherapy
experienced VF
– 9 of 11 had genotypic INSTI resistance at VF
– INSTI resistance pathways varied: 92Q/155H (n = 1);
97A/155H (n = 1); 155H/148R (n = 1); 118R (n = 2);
148K (n = 1); 148H (n = 2); 148R (n = 1)
Blanco JL, et al. CROI 2017. Abstract 42. Slide credit: clinicaloptions.com

34
DRIVE-FORWARD Study:
Doravirine + 2 NRTIs in Treatment-Naïve Patients
Doravirine + FTC/TDF or ABC/3TC
(n=383)
Darunavir/r + FTC/TDF or ABC/3TC
(n=383)
Week 0 96
Randomization
1:1
48
Primary Endpoint
(FDA snapshot)
Phase 3
(Double-Blind)
Treatment-naive
HIV RNA ≥1000 copies/mL
No resistance to study drugs
Stratified by:
HIV RNA >100K copies/mL
NRTI choice
Doravirine (next-generation NNRTI) 100 mg qd. Unique resistance profile, low DDI potential, no
food or PPI effects
Darunavir/r: 800/100 mg.
Non-inferiority margin: 10%.
Mean age: 35-36 years.
Male: 84%; Black: 22%.
Mean HIV RNA: 4.4 log10 copies/mL.
HIV RNA >100K copies/mL: 21%.
Mean CD4 count: 412-433 cells/mm3.
NNRTI choice:
FTC/TDF: 87%.
ABC/3TC: 13%.

3535
DRIVE-FORWARD Study: Treatment Outcomes at
Week 48 With Doravirine + 2 NRTIs
• Doravirine was non-inferior to
darunavir/r
– Similar results regardless of baseline
HIV RNA level, CD4 count, or choice of
NRTI combination
• Similar CD4 gains for doravirine and
darunavir/r (193 versus 186
cells/mm3)
• No genotypic or phenotypic
resistance among protocol-defined
failures
Patients(%)
0
20
40
60
80
100 84%
3.9 (-1.6, 9.4)
80%
Doravirine +
FTC/TDF or
ABC/3TC
(n=383)
Darunavir/r +
FTC/TDF or
ABC/3TC
(n=383)

3636
DRIVE-FORWARD Study:
Safety at Week 48 With Doravirine + 2 NRTIs
• Doravirine was generally well
tolerated and safe
events: 2%
• No discontinuations due to
neuropsychiatric adverse events
• Rash (n=2)
– Most common adverse events:
diarrhea, headache, neuropsychiatric,
nausea
• Superior lipid profile for fasting LDL-C
compared with darunavir/r
• Low rate of grade 3/4 laboratory
abnormalities (1%-2%)
Doravirine
(n=383)
Darunavir/r
(n=383)
Discontinuations due to
adverse events (%)
2 3
Adverse events (%)
Diarrhea
Headache
Neuropsychiatric
Nausea
Rash
14
14
11
11
7
22
11
13
12
8
Change in fasting
lipids (mg/dL)
Total cholesterol
HDL-C
Triglycerides
-4.5*
3.9
-3.1
9.9
4.2
21.9
Safety at Week 48
*P<0.0001 versus darunavir/r.

37
Study 1475: Bictegravir or Dolutegravir + FTC/TAF in
HIV Treatment-Naïve Patients
Sax PE, et al. 24th CROI. Seattle, 2017. Abstract 41.
Sax PE, et al. Lancet HIV. 2017;Feb 14. [Epub ahead of print].
Bictegravir + FTC/TAF qd
(n=65)
Dolutegravir + FTC/TAF qd
(n=33)
Week 0 48
Randomization
2:1
24
Primary Endpoint
(FDA snapshot)
Phase 2
(Double-Blind)
Treatment-naive
CD4 ≥200 cells/µL
No HBV or HCV coinfection
Bictegravir: novel, once-daily, unboosted integrase inhibitor.
FTC/TAF: emtricitabine/tenofovir alafenamide.
After week 48, all patients who completed the double-blind phase entered an extension phase and received open-label
bictegravir/emtricitabine/tenofovir AF.
Male: 96%.
White: 57%.
Median HIV RNA: 4.4 log10 copies/mL.
HIV RNA >100K copies/mL: 17%.
Median CD4 count: 441-445 cells/mm3.
Median eGFR: 122-130 mL/min.

3838
Study 1475: Treatment Outcomes With Bictegravir or
Dolutegravir + FTC/TAF for Initial ART
• Bictegravir + FTC/TAF
– Greater proportion achieving HIV
RNA at week 24 and 48 versus
dolutegravir + FTC/TAF
• No difference in CD4 gain between
the 2 arms at week 48
– Bictegravir: 258 cells/mm3
– Dolutegravir: 192 cells/mm3
• No INSTI or NRTI treatment-
emergent resistance was detected
in either treatment arm at week 48
Patients(%)
0
20
40
60
80
100 97%
Week 24 Week 48
97%
94%
91%
2.9 (-8.5, 14.2)
6.4 (-6.0, 18.8)
Bictegravir (n=65) Dolutegravir (n=33)

3939
Study 1475: Safety at Week 48 With Bictegravir or
Dolutegravir + FTC/TAF for Initial ART
• Both bictegravir and dolutegravir +
FTC/TAF were safe and well
tolerated over 48 weeks
events (n=1 in the bictegravir arms
due to urticaria in a patient with a
history of urticaria and atopic
dermatitis)
• No discontinuations due to renal
adverse events and no tubulopathy
in either treatment arm
• 4 phase 3 studies with
bictegravir/FTC/TAF are ongoing
Bictegravir
(n=65)
Dolutegravir
(n=33)
Adverse events (%)
Diarrhea
Nausea
Headache
Upper RTI
Fatigue
Arthralgia
12
8
8
6
6
6
12
12
3
0
6
6
Grade 2-4 laboratory
abnormalities (%)
Creatine kinase
AST
Hyperglycemia
ALT
LDL-C
13
9
8
6
6
9
3
13
0
9
Change in eGFR
(mL/min)
-7.0 -11.3
Safety at Week 48

40
LATTE Study: Long-Term Efficacy and Safety of Cabotegravir +
Rilpivirine as 2-Drug Oral Maintenance Therapy
Margolis DA, et al. 24th CROI. Seattle, 2017. Abstract 442.
Efavirenz + 2 NRTIs*
Cabotegravir (10, 30,
60 mg) + 2 NRTIs*
Phase 2b study
(96 weeks)
Treatment-naïve
Open-label
CD4 ≥200 cells/mm3
Stratified by
HIV RNA and NRTI
Week 0 24 96 144
Cabotegravir (10, 30, 60 mg)
+ Rilpivirine
Induction
(24 weeks)
Maintenance
(72 weeks)
Cabotegravir: novel integrase inhibitor that is a dolutegravir analogue (oral and injectable formulations).
*Emtricitabine/tenofovir DF or abacavir/lamivudine.
Patients in the cabotegravir arm with HIV RNA <50 copies/mL at week 20 were switched to a maintenance regimen at week 24.
Cabotegravir 30 mg
+ Rilpivirine
Open-Label
Phase

4141
LATTE Study: Long-Term Efficacy and Safety of Cabotegravir +
Rilpivirine as 2-Drug Oral Maintenance Therapy
• Oral cabotegravir + rilpivirine provided
durable virologic suppression through
144 weeks of treatment
– Few virologic failures (n=3) during the
open-label phase
• Overall cabotegravir + rilpivirine was
safe and well tolerated
– Discontinuations due to adverse events
(3%)
• Data support further study of
cabotegravir 30 mg + rilpivirine 25 mg
as an oral lead-in and/or oral bridging
supply for long-acting cabotegravir IM
based therapy
Margolis DA, et al. 24th CROI. Seattle, 2017. Abstract 442.
Cabotegravir +
Rilpivirine
Virologic outcomes (n=181)
HIV RNA <50 copies/mL (%; ITT-E)
Protocol-defined virologic failure (%)
67
5
Safety (n=160)
Discontinuations due to adverse events (%)
Grade 2-4 drug-related adverse events (%)
Grade 3-4 laboratory abnormalities (%)
Creatine kinase
ALT
Lipase
Total neutrophils
3
4
8
<1
4
3
Key Outcomes at Week 144

4242
GS-CA1 HIV Capsid Inhibitor:
More Potent Than Approved Antiretrovirals
• Novel HIV capsid inhibitor
• Inhibits multiple steps in the HIV
replication cycle
– Capsid core assembly
– Capsid core disassembly
– Nuclear translocation
• Highly active against major HIV-1
mutants selected by clinical PIs,
NRTIs, NNRTIs, and INSTIs
• No measurable cytotoxicity in target
and non-target primary cells
• Single sc injection maintains plasma
concentrations 9 times the paEC95 for
>10 weeks
Tse WC, et al. 24th CROI. Seattle, 2017. Abstract 38.
GS-CA1: Multiple Sites of Action
CD4+ T
Lymphocytes Macrophages
Human
PBMCs
GS-CA1 60 100 140
Efavirenz 1200 2300 --
Dolutegravir 1000 1900 1200
Atazanavir 6900 8300 19,000
EC50 (pM)

Agent
MoA or
Formulation
Phase
Dosing/
Administration
Implications
GS-CA1[1] HIV capsid inhibitor
Pre-
clinical
Extended release,
suitable for SC of solid
depot formulation
 Potent ART with orthoganol resistance profile to
existing ART; potential for long-acting formulation
due to low aqueous solubility, high stability
GS-9131[2] NRTI
Pre-
clinical
Potential for once daily
dosing
 Potent ART active against NRTI RAMs K65R, L74V,
M184V alone or in combination; minimal loss of
susceptibility with 4 or more TAMs
MK-8591[3]
Nucleoside
Reverse
Transcriptase
Translocation
Inhibitor (NRTTI)
I
10 mg QW PO;
potential for extended
duration
 Comparable MK-8591 levels in animal rectal,
vaginal tissue to TDF levels in tissues of human
subjects highlights potential prophylaxis utility
GS-PI1[4] PI
Pre-
clinical
Potential for
unboosted, once daily
dosing
 Potent ART with high barrier to resistance, including
< 2-fold loss in potency against major PI RAMs,
and 10-fold to 40-fold longer in vivo half life vs ATV
or DRV
NANO-EFV,
NANO-
LPV[5]
Oral, lower dose
SDN
I
nEFV: 50 mg QD, 21 d
nLPV/RTV: 200/100
mg BID, 7 d
 Enhanced oral bioavailability suggests can reduce
EFV, LPV dose by ~ 50% while maintaining PK
Additional Investigational Agents Reported
at CROI 2017: Preclinical and Phase I
1. Tse WC, et al. CROI 2017. Abstract 38. 2. White KL, et al. CROI
2017. Abstract 436. 3. Grobler J, et al. CROI 2017. Abstract 435.
4. Link JO, et al. CROI 2017. Abstract 433. 5. Owen A, et al. CROI
2017. Abstract 39. Slide credit: clinicaloptions.com

Additional Investigational Agents
Reported at CROI 2017: Phase II
1. Bekker L-G, et al. CROI 2017. Abstract 421LB. 2. Murphy R, et al.
CROI 2017. Abstract 452LB. 3. Wang C-Y, et al. CROI 2017. Abstract
450LB.
Agent
MoA or
Formulation
Phase
Dosing/
Administration
Implications
TMC278 LA[1] LA injectable
RPV (IM)
II 1200 mg IM Q8W  Potential as injectable, long-acting PrEP
Elsulfavirine[2]
Prodrug of
new NNRTI
VM1500A
IIb
Combined
therapy:
20 mg
elsulfavirine +
FTC/TDF PO QD
 Less toxic alternative to EFV for initial
ART
UB-421[3] Anti-CD4
receptor mAb
II
10 mg/kg QW IV
or
25 mg/kg Q2W IV
 Possible ART alternative for
maintenance therapy in virologically
suppressed pts

4545
Program Overview
• HIV prevention

4646
SMART and START Studies: Benefit of
Immediate/Continuous ART on Disease Risk
Borges AH, et al. 24th CROI. Seattle, 2017. Abstract 474.
• Combined analysis of SMART and
START studies (n=10,157)
– AIDS events (n=123)
– Serious non-AIDS events (n=244)
– CVD (n=103)
– Cancer (n=117)
– Death (n=118)
– AIDS and serious non-AIDS events
(n=359)
• Immune preservation through immediate
and continuous ART significantly reduces
the risk of AIDS and non-AIDS events
– Cancer risk reduction did not vary by
type of cancer
Hazard Ratio for
Reducing Risk of Events
AIDS
Serious
non-AIDS events
CVD
Cancer
Death
AIDS or serious
non-AIDS event
0.5 1.0 2.0 5.0 10
Favors Immediate and
Continuous ART

D:A:D: Exposure to ATV/RTV or DRV/RTV
and Risk of CVD
 Prospective analysis of pts followed
from 1/1/2009 (BL) to earliest CVD, last
visit + 6 mos, or 2/1/2016 (N = 35,711)
– 1157 pts (3.2%) developed CVD (MI,
stroke, sudden cardiac death, invasive
CV procedure)
 Cumulative expos. to DRV/RTV, but not
ATV/RTV, assoc. with increased CVD
risk in multivariate analysis: 59% risk
increase per 5-yrs’ DRV/RTV
– Assoc. does not appear to be mediated
through dyslipidemia
 Limitations: potential for unmeasured
confounding; observational study;
unable to distinguish between DRV/RTV
800/100 mg QD vs DRV/RTV 600/100
mg BID
Ryom L, et al. CROI 2017. Abstract 128LB.
CVD Risk per 5 Yrs of ARV Exposure, IRR (95% CI)
Model ATV/RTV DRV/RTV
Univariate 1.25 (1.10-1.43) 1.93 (1.63-2.28)
Multivariate
 Baseline adjusted* 1.03 (0.90-1.18) 1.59 (1.33-1.91)
 Time-updated
adjusted* 1.01 (0.88-1.16) 1.53 (1.28-1.84)
*Adjusted for: BMI, CKD, DM, CD4, dyslipidemia.
Relationship Between 5-Yr Exposure
to ARVs and CVD
ATV/RTV DRV/RTV
2.5
2.0
1.5
1.0
0.5
0.0
CVDIncidenceRate
Ratio(95%CI)
No exposure
Univariate
MV: BL adj model
MV: Time-updated adj model

4848
D:A:D Cohort: Summary of the Cardiovascular
Disease Risk and Use of Contemporary PIs
• Cumulative use of darunavir/r but not atazanavir/r was independently
associated with a small but gradually increasing risk of CVD (59% per 5
years exposure)
– Associations unchanged whether darunavir/r was used
• As a first-ever PI/r-based regimen or not
• With NRTI or not
• The strength of the darunavir/r association
– Similar in size compared with indinavir and lopinavir/r
– Does not appear to be modified by dyslipidemia
• Cautious interpretation is warranted due to the observational study design
Ryom L, et al. 24th CROI. Seattle, 2017. Abstract 128LB.

4949
NA-ACCORD Cohort: Impact of Smoking, Hypertension,
and Cholesterol on MI in HIV-Infected Adults
• NA-ACCORD cohort (2000-2013)
– HIV-positive adults (n=29,515)
– Median follow-up: 3.5 years
• Number of validated, first occurrence,
type 1 MIs: 347 over 131,137 person-
years of follow-up
• Key outcome: population attributable
fractions (PAF)
– The proportion of MIs that could be
avoided in HIV-infected adults if all were
unexposed to the modifiable risk factor of
interest (holding other variables constant)
Althoff KN, et al. 24th CROI. Seattle, 2017. Abstract 130.
Type 1 MIs: MIs from plaque rupture that would be most susceptible to traditional MI risk factors.
No MI
(n=29,168)
MI
(n=347)
Age, years (%)
≤40
41-49
50-59
≥60
47
35
14
3
18
33
31
10
Male (%) 80 86
White/black/Hispanic 46/37/11 56/35/6
ART-naïve (%) 39 26
Modifiable risk factors (%)
Smoking
Elevated triglycerides
Treated hypertension
Diabetes
Stage 4 CKD
CD4 <200 cells/mm3
Clinical AIDS progression
HCV infection
75
25
10
3
2
24
57
22
18
84
61
26
8
6
32
53
31
27
Baseline Characteristics

50
NA-ACCORD Cohort: Impact of Smoking, Hypertension,
and Cholesterol on MI in HIV-Infected Adults
Althoff KN, et al. 24th CROI. Seattle, 2017. Abstract 130.
0
10
20
30
40
50
Adjusted PAFs for MI
(29,515 HIV-positive adults followed for a median of 3.5 years)
PAFs(%)
Smoking Total
Cholesterol
Hypertension CD4 HIV RNA
38%
43%
41%
10%
6%
2%
AIDS
Adjusted for age, sex, race, smoking, total cholesterol, hypertension, diabetes, chronic renal disease, CD4, HIV RNA,
AIDS, and HCV.

Review from the 24th Conference on Retroviruses and Opportunistic Infections (CROI) – 2017

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Review from the 24th Conference on Retroviruses and Opportunistic Infections (CROI) – 2017