Clinical cases: Genetic barrier to HIV resistance

Roger Paredes, MD, PhD

Infectious Diseases Service & irsiCaixa

Hospital Germans Trias i Pujol

Badalona, Catalonia, Spain

Disclosure

• Roger Paredes has received grant support and has participated in advisory meetings from Gilead, MSD and ViiV healthcare

Joe, 32

• 32-year-old, Western European

• MSM, Chemsex

• Several treatments for syphilis & Chlamydia trachomatis

• No PrEP officially available in his country

• Tested because partner diagnosed with HIV-1 infection

• No symptoms at diagnosis

Joe, 32

CD4+ 462 cells/mm3

VL 78000 copies/mL

• Hepatitis B & C negative

• HLA B57*01 negative

• RPR ½

• Normal blood counts, liver and renal function

• Let’s treat him!

Which of the following is a a suboptimal first-line ART option

1. TAF/FTC/Bictegravir

2. TAF/FTC/Darunavir

3. ABC/3TC/Dolutegravir

4. 3TC/Dolutegravir

5. TDF/XTC/Efavirenz

6. None

EACS 9.1 –October 2018

1st-line ART

Recommended Alternative

ABC/3TC/DTG ABC/3TC

TAF/FTC or TDF/FTC RAL

DTG EFV

RAL ATVb

RPV TDF/FTC/EFV

DRVb TAF/FTC or TDF/FTC

ELVc

ATVb

DTG + 3TC

RAL + DRV b

DHHS guidelinesOct 25, 2018

Assuming no PrEP and resistance test available. Would you do a resistance test before starting ART?

1. Yes, always

2. No, I would first start ART, order a resistance test, and review theresistance test results later.

3. Resistance tests are useless because there’s almost no transmittedresistance

4. Resistance tests are useless, because drugs work so well that theyare able to suppress transmitted drug-resistant viruses

5. 2 and 4

Are you afraid that the activity of any of these drugsmay be compromised by PDR?

1. XTC

2. TDF

3. XTC and TDF

4. INSTIs

5. NNRTIs

6. bPI

7. I’m not scared. Bring them on!

Are you afraid that the activity of any of these drugsmay be compromised by PDR?

1. XTC

2. TDF

3. XTC and TDF

4. INSTIs

5. NNRTIs

6. bPI

7. I’m not scared. Bring them on!

Petersen A, et al. Characterisation of HIV-1 transmission clusters and drug-resistant mutations in Denmark, 2004 to 2016 . Eurosurveillance 2018

PI: protease inhibitor. NNRTI: non-nucleos(t)ide reverse transcriptase inhibitor. NRTI: nucleos(t)ide reverse transcriptase

inhibitor. P-value by Chi-squared test or Fisher’s exact test as appropriate.

9.7

2.5

4.5 4.1

6.9

2.01.4

4.2

0%

3%

6%

9%

12%

15%

Any drugclass

PI NRTI NNRTI

% o

f p

ati

en

ts

B (N=2,992) non-B (N=1,331)

Evaluation of TDR in the overall population and according to subtype among 4,323 individualswith HIV-1 infection confirmed in different counselling and testing centres in North and Central Italyfrom 2000 to 2014.

Overall TDR prevalence was 8.8% (N=382). TDR was higher in B subtype infected patients than in those infected

with non-B subtypes (9.7% vs. 6.9%, p=0.003).

Fabeni et al., JAC 2017,

Fabeni et al., JAC 2017,

The prevalence of M184V is very low regardless subtype

Prevalence of drug resistance mutations in HIV-1 B (A) and non-B subtypes (B) according to drug classes and presence or not in TransmissionClusters (TCs). Each bar is divided according to: 1) the presence of drug resistance mutations in clusters with ≥3 sequences (black part), 2) thepresence of drug resistance mutations in pairs (marked part), 3) the presence of drug resistance mutations out of clusters (white part).

Prevalence of resistance mutations in the 4,323 sequences from drug naive individuals diagnosed in north and central Italy between 2000 and 2014, according to subtype.

• “For people starting DTG (BIC)-based regimens in the US, obtaining a baseline genotype offersminimal clinical benefit.

• Baseline genotypes provide no benefit to mostadults with a new HIV diagnosis and only a verysmall increase in projected survival to those whodo benefit.

• This analysis projects a mean gain of <1 QALD among all people starting ART. At $320/test, thisresults in an ICER of $420,000/QALY, which offerspoor value relative to other HIV interventions

• A resistance genotype at HIV diagnosis in the US isnot cost-effective;

• Inclusion of this test in baseline evaluation of adults newly diagnosed with HIV should be reconsidered. “

If Joe was taking PrEPWould you be afraid of PDR?

1. No. Clinical trials show that resistance selection during PrEP isnegligible.

2. Yes, but rates of PDR are very low. I would start ART asap, order a resistance test, and review resistance test results later.

3. Yes. Rates of PDR are high after PrEP. I would wait to the resistancetest before I start ART

If Joe was taking PrEP with TDF/FTCWhich drugs on a first-line regimen would you expect to be compromised, if any?

1. None

2. XTC

3. TDF

4. XTC and TDF

5. INSTIs

30% of new infections among PrEP users in NYC show drug resistance (M184V) vs 2% in never-PrEP users

PrEP Users

Resistant WT

Never-PrEP Users

Resistant WT

Misra et al. CROI 2019. Abstract 107

4 K65R all in never PrEP users

What would be your first ART choice if you suspect pre-existing M184V?

1. TAF/FTC/Bictegravir

2. TAF/FTC/Darunavir/c

3. TAF/FTC/Bictegravir + Darunavir/c

4. 3TC/Dolutegravir

Are DTG or BIC available for 1st-

line ART?

YesWe (mainly) worry about

M184V

NoWe worry about NNRTI DRMs and

M184V

3TC and FTC select M184I/V in vitro → >100 fold-change

Additional effects of M184V• increases susceptibility to other NRTIs

• to zidovudine (ZDV), stavudine (d4T) and tenofovir (TDF and TAF)

• affects the catalytic function of RT• decreases processivity resulting in low viral fitness

• residual antiviral activity, even in the presence of 3TC monotherapy, in patients who harbor the M184V/I substitution

• enhances fidelity of HIV RT• purified M184V variant proteins have exhibited 2- to 6-fold reduced mutation frequency compared

with wild-type RT

• contribution to the reduced rate of drug resistance once have been selected

Orkin C (Abs. P021). JIAS 2018; 21 , suppl. 8: 31

9290

9194

9393

7993

8990

9194

9293

8891

9294

8484

9494

9395

8892

> 100 000

≤ 100 000

> 200

≤ 200

≥ 50

35 to < 50

< 35

Female

Male

African heritage

Asian

White

Other

717

140153

576564

653662

6355

49

668

6580

231229

420408

11398

603619

9976

7172

480497

6672

Baseline HIV-1 RNA,copies/ml

Baseline CD4+ count,cells/mm3

Age

Sex

Race

n

0 100604020 80

HIV RNA < 50 c/mL at W48 (%) in subgroups of the pooled analysis Difference, % (95%CI)

-2.8

1.9

-1.5

-13.4

-0.7

-3.0

-0.8

-2.3

-1.6

-0.4

-0.1

-3.8

0 10 20 30-10-20-30

-1.7

DTG + TDF/FTC DTG + 3TCDTG + TDF/FTCDTG + 3TC

GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line

www.arv-trials.com

* Reasons for snapshot non-response in participants with baseline CD4 < 200/mm3

DTG + 3TC (N = 13):

3 with HIV RNA > 50 c/mL, 1 confirmed virologic withdrawal, 2 discontinuations for non-treatment-related adverse event, 2 protocol violations, 2 lost to follow-up, 1 withdrew consent, 1 withdrew to start HCV treatment, 1 change in ART due to incarceration

DTG + TDF/FTC (N = 4): 1 with HIV RNA > 50 c/mL, 1 lost to follow-up, 1 withdrew consent, 1 investigator discretion

Time to Target notdetected (TND)

Gemini 1&2

Conference on Retroviruses and Opportunistic Infections; March 4-7, 2019; Seattle, WA

Introduction

The GEMINI-1 and -2 studies in treatment-naive adults with screening

HIV-1 RNA ≤500,000 c/mL showed dolutegravir + lamivudine (DTG +

3TC, 2DR) was non-inferior to DTG + tenofovir disoproxil fumarate/

emtricitabine (DTG + TDF/FTC, 3DR) at Week 48 by FDA Snapshot

algorithm; 91% (655/716) in the 2DR arm vs 93% (669/717) in the

3DR arm achieved HIV-1 RNA <50 c/mL.1

Low rates of virologic withdrawal were observed at Week 48 in both the

DTG + 3TC and DTG + TDF/FTC arms; respectively, 6 and 4 participants

met these criteria in the DTG + 3TC and DTG + TDF/FTC arms, and no

participants in either arm had treatment-emergent INSTI or NRTI mutations.1

Abbott RealTime HIV-1 assay used in the studies measures viral load

(VL) from 40 to 10,000,000 c/mL, and provides qualitative target detected

(TD) or target not detected (TND) for VL <40 c/mL.

Clinical and subject management implications of more stringent low-level

VL data need clarification. We assessed the proportion of participants

with TND over time and by baseline (BL) VL for 2DR vs 3DR.

Figure 3. Kaplan-Meier Plots of Time to TND: Overall Participants

and by Baseline HIV-1 RNA Subgroup

Overall, median (95% CI) time to TND was 57 (NE, NE) days for 2DR vs 57 (57, 58) days for 3DR.

For the BL ≤100,000 c/mL stratum, median (95% CI) time to TND was

57 (56, 57) days for both 2DR and 3DR.

For the BL >100,000 c/mL stratum, median (95% CI) time to TND was shorter for 2DR at 113 (88, 168) days vs 169 (168, 248) days for 3DR.

Table 1. Proportion of Participants With TND at Week 48 (Snapshot

Analysis) by Baseline Plasma HIV-1 RNA Levels

Discussion

The suppression of HIV-1 RNA VL in plasma is overall recognised as

predictive of antiretroviral regimen success and when elevated may

predict HIV evolution and emergence of resistance.2

More sensitive measures of HIV-1 RNA levels for patient management

are exploratory. Additional analyses of low-level qualitative or quantitative

HIV-1 RNA may be useful for optimising treatment/patient management.

Methods

Participants were randomised 1:1 to treatment with 2DR or 3DR. The

proportion of participants with HIV-1 RNA <40 c/mL and TND status at

Week 48 was analysed using a Cochran-Mantel-Haenszel test stratified

by plasma HIV-1 RNA (≤100,000 vs >100,000 c/mL) at BL and study.

Proportion of participants with HIV-1 RNA <40 c/mL and TND status were

summarised by visit and at Week 48 by BL HIV-1 RNA subgroup. Time to

TND status overall and by BL HIV-1 RNA subgroup were estimated using

non-parametric Kaplan-Meier method.

490

Mark Underwood,1 Rimgaile Urbaityte,2 Jörg Sievers,3 Choy Man,1 Ruolan Wang,1 Brian Wynne,1 Allan Tenorio,1 Alexander Currie,2 Keith Pappa,1 Justin Koteff,1 Martin Gartland,1 Michael Aboud3

1ViiV Healthcare, Research Triangle Park, NC, USA; 2GlaxoSmithKline, Stockley Park, UK; 3ViiV Healthcare, Brentford, UK

HIV Replication at <40 c/mL for DTG + 3TC vs DTG + TDF/FTC in the GEMINI-1 & -2 Studies

Acknowledgments: This study was funded by ViiV Healthcare. We thank everyone who has

contributed to the success of these studies, including all study participants and their families; the

GEMINI-1 and GEMINI-2 clinical investigators and their staff; and the ViiV Healthcare and GSK study

teams. Editorial assistance and graphic design support for this poster were provided under the direction

of the authors by MedThink SciCom and funded by ViiV Healthcare.

References: 1. Cahn et al. Lancet. 2019;393:143-155. 2. Ryscavage et al. Antimicrob Agents

Chemother. 2014;58:3585-3598.

Conclusions

Similar proportions of participants in the DTG + 3TC and DTG +

TDF/FTC arms had TND by Snapshot at all weeks.

Snapshot response rates based on TND status at Week 48 were

similar between arms for the BL ≤100,000 c/mL subgroup and

numerically higher for DTG + 3TC in the BL >100,000 c/mL subgroup.

Median time to TND was similar overall and in the BL VL

≤100,000 c/mL subgroup and less for DTG + 3TC vs DTG +

TDF/FTC if >100,000 c/mL at BL.

These data, utilising a more stringent but exploratory TND Snapshot

criterion, continue to demonstrate the effectiveness and potency of

DTG + 3TC in treatment-naive participants.

DTG + 3TC (N=716)

Day

1

Screening

(28 d)

DTG + TDF/FTC (N=717)

DTG + 3TC

Week

48

Double-blind

phase

Open-label

phase

Continuation

phase

Week

144

Week

24

Week

96

ART-naive adults

VL 1000-500,000 c/mL

1:1

Figure 1. GEMINI-1 and GEMINI-2 Study Design

Identically designed, randomised, double-blind, parallel-group, multicentre, non-inferiority studies.

24

6

37

5

42

8

425

46

6

46

5

55

3

22

8

35

1

41

0

402

45

3

48

4

525

0

10

20

30

40

50

60

70

80

90

4 8 12 16 24 36 48

Pro

po

rtio

n o

f p

art

icip

an

ts

Week

DTG + 3TC DTG + TDF/FTC

Figure 2. Proportion of Participants With TND by Visit:

Snapshot Analysis

At Week 48, similar proportions of participants had Snapshot TND in the

2DR and 3DR arms (77% [553/716] vs 73% [525/717]; adjusted difference,

3.8%; 95% CI, ≤0.6% to 8.2%).

Proportions were also similar at Weeks 4 (34% vs 32%), 8 (52% vs 49%),

12 (60% vs 57%), 16 (59% vs 56%), 24 (65% vs 63%), and 36 (65% vs 68%).

Results

Responses to TND were similar for participants with BL VL ≤100,000 c/mL.

Responses to TND were numerically higher for 2DR vs 3DR arms for

participants with BL VL >100,000 c/mL. By study:

GEMINI-1 response to TND: 2DR = 51/74 (69) and 3DR = 34/76 (45).

GEMINI-2 response to TND: 2DR = 39/66 (59) and 3DR = 45/77 (58).

Primary

endpoint

Participants with HIV-1 RNA <40 c/mL and missing interpretation for Target Detected (TD)/

Target Not Detected (TND) status are assumed to be TD.

Baseline VL strata (c/mL)

DTG + 3TC n/N (%)a

DTG + TDF/FTC n/N (%)a

Treatment difference(95% CI)b

≤100,000 463/576 (80) 446/564 (79) 1.3 (≤3.4 to 6.0)

>100,000 90/140 (64) 79/153 (52) 12.7 (1.4 to 23.9)

>250,000 25/51 (49) 20/46 (43) 5.5 (≤14.3 to 25.4)

>400,000 5/18 (28) 6/24 (25) 2.8 (≤24.2 to 29.8)

aNumber responded/Number assessed (%). bUnadjusted proportion of DTG + 3TC ≤ proportion of

DTG + TDF/FTC (95% CI).

Kaplan-Meier Time to Suppression (Plasma HIV-1 RNA <50 c/mL)

Median time to HIV-1 RNA <50 c/mL was 29 days for both arms when BL

VL ≤100,000 c/mL and 57 days for both arms when BL VL >100,000 c/mL.

Figure 4. Kaplan-Meier Plots of Time to TND: By Baseline HIV-1

RNA >100,000 c/mL for GEMINI-1 and GEMINI-2

GEMINI-1 median (95% CI) time to TND: 2DR = 93 (85, 168) days;

3DR = 169 (115, 252) days.

GEMINI-2 median (95% CI) time to TND: 2DR = 118 (113, 169) days;

3DR = 169 (133, 256) days.

Main worries about DTG+3TC as 1st-line

M184V

CD4<200Reservoir Yes, but…Studies in late presenters are needed

Underinvestigation

Starts TDF/FTC+DTG

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1000

10000

100000

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

VL CD4+

After 2 years, bone and renal toxicity. TAF not available. what can you do?

1. DTG alone

2. DTG + 3TC

3. DRVb monotherapy

4. DRV + RAL

5. Pray to the Virgin Mary

Ciaffi L, HIV Glasgow 2016, Abs. O122

Virological success

PI/r + 3TC

PI/r

HR = 0,11 (IC 95 % : 0,04 - 0,32)

p < 0,0001

%

0

20

40

60

80

100

132 132 131 129 128IP/r + 3TC133 133 127 112 103IP/r

Patients at risk

0 12 24 36 48Weeks

Essai MOBIDIP-ANRS 12286 : Bithérapie de maintenance avec IP/r + 3TC. Résultats à S48 (3)

117

Gagliardi R, et al. Impact of previous M184V on virologic outcome of switch to 3TC-based dual therapies. CROI 2018; Boston. Abstract 498.

Baseline M184V Not Associated With Increased Probability of Virologic Failure in Virologically Suppressed Italian Patients Switching to Lamivudine-Based Dual Therapy

Viral dynamics during DTG monotherapy maintenance failure

Slide Courtesy of Charles Boucher, Erasmus University

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10 years on NNRTI 3-drug ART

Blanco JL, et al EACS 2017

Summary

• M184V is the most frequent mutation involved in genetic barrier discussions

nowadays

• Rare if spontaneous transmission

• Up to 30% of new diagnoses in subjects with previous PrEP (NYC data)

• DTG and BIC: Higher genetic barrier tan RAL or ELV, but not as high as bPI.

• Failure to DTG monotherapy with “RAL-like” resistance profiles

• DTG + 3TC

• As first-line: only if WT virus & >200 cells/mm3→ Gemini 1 &2 studies excluded M184V subjects

• As switch: likely effective even in the presence of M184V

• Only 1 single case of resistance emergence at failure (A5353)

Slides: Vincent Calvez, CF Perno