HIV Drug Resistance in 2018

“How Can We Deal With It?”

Ghassan Wali, MDHead, Infectious Diseases section

HIV physicianKing Faisal specialist and research center, Jeddah

Objectives:

Review the prevalence of transmitted drug resistance locallyand internationally.

Go over the most important mutations and their clinicalimplications

Identify key points of managing antiretroviral drugs therapyin HIV patients who are treatment-experienced.

Apply evidence from recent clinical trials to managingpatients who are failing second and third line therapy.

Patient HAge 41

HIV Status Positive; 2 days ago

CD4 420

HIV RNA 100K per ml

eGFR 110

Co-infection HBsAg: positive

comorbidities hypertension

Metabolism hyperlipidemia

medications Amlor, lipitor

HIV genotype test pending

Patient is referred

from infertility

clinic

• What is your decision today at the clinic:

• 1- uphold ARV until genotype testing is back

• 2- start him on atazanavir/r plus TAF/FTC

• 3- Start him on Darunavir/r plus TAF/FTC

• 4- start him on raltegravir plus TAF/FTC

• 5- start him on dolutegravir plus TAF/FTC

• 6- I have a different answer

Recommendations for HIV resistance testing

Prevalence of Drug Resistance Mutations in Treatment-Naive Patients, 2000-2013

Baseline plasma samples from 4 phase III trials (GS 903, 934, 104, 111)◦ 1617 samples analyzed for

integrase mutations◦ 2531 analyzed for protease or

RT mutations

Substantial in prevalence of NNRTI resistance, modest in PI resistance

Stable prevalence of NRTI resistance (mostly TAMs)◦ M184V/I 0.2%; K65R 0.2%

▪Little evidence of transmitted INSTI resistance over period◦ Mostly T97A polymorphism

Margot NA, et al. CROI 2014. Abstract 578.

2000 (GS-903)

2003 (GS-934)

2013 (GS-104/GS-111)

0Pts

With M

uta

tion

s a

t B

L (

%)

2

NNRTI

10

4

6

8

NRTI PI INSTI

0.5 1.0

0

4.2

8.7

3.22.6 2.6

1.2

2.4

2.9

1.4

Prevalence of Transmitted MDR HIV in the US: Selected Studies

Transmission of HIV resistant to a single class of ARV more common than HIV resistant to multiple classes[1,3]

◦ 13.6%, 2.1%, and 0.5% of transmitted HIV resistant to 1, 2, and 3 ARV classes, respectively[3]

1. Baxter JD, et al. HIV Med. 2015;16:77-87. 2. INSIGHT START Study Group.

N Engl J Med. 2015;373:795-807. 3. Kim D, et al. CROI 2013. Abstract 149.

Prevalence of Transmitted Drug-

Resistant HIV

(2009-2013), %[1-3]

Overall

▪ NRTI

▪ NNRTI

▪ PI

12.6-16.2

3.7-6.7

8.1-8.4

2.0-4.5

Decrease in Prevalence of MDR HIV in the US in Recent Era of HIV Treatment

• Assessment of phenotypic drug resistance patterns in US samples submitted to Monogram Biosciences for HIV resistance testing from 2003-2012 (N = 62,397)

Paquet AC, et al. Antivir Ther. 2014;19:435-441.

60

0

10

20

30

40

50

2-Class Resistance

PI and NRTIPI and NNRTINRTI and NNRTI

0

10

20

30

40

50

603-Class Resistance

1-Class Resistance

0

10

20

30

40

50

60

Resis

tant S

am

ple

s (

%)

PINRTINNRTI

Causes of Treatment Failure

DHHS Guidelines.

Poor adherence

Insufficient drug level

Viral replication in the presence of drug

Resistant virus

Social/personal issuesRegimen issues

Toxicities

Suboptimal potency

Wrong dose

Host genetics

Poor absorption

Rapid clearance

Poor activation

Drug interactions

Virologic failure

Transmitted or Acquired

• In case you need to start the patient on ARV before genotype test is readily available, use a PI-based ( boosted-darunavir) or high genetic barrier INSTI ( dolutegravir)

DHHS Guidelines.

• What is your decision today at the clinic:

• 1- uphold ARV until genotype testing is back

• 2- start him on atazanavir/r plus TAF/FTC

• 3- Start him on Darunavir/r plus TAF/FTC

• 4- start him on raltegravir plus TAF/FTC

• 5- start him on dolutegravir plus TAF/FTC

• 6- start him on dolutegravir plus darunavir/cobi

DHHS: Recommendations for Resistance Testing

• Results used to inform design of new ART regimens for pts experiencing VF

DHHS Guidelines.

Question Recommendation

Who should receive

resistance testing?

▪ Pts with VF and HIV-1 RNA levels > 1000 copies/mL

▪ May be considered for pts with 500-1000 copies/mL

When should testing be

conducted?

▪ While on failing ART regimen or < 4 wks from treatment end

▪ May still be considered after 4 wks

What types of testing

should be conducted?

▪ First-/second-line failure: genotypic testing

▪ Suspected MDR: genotypic plus phenotypic testing

▪ When considering CCR5 antagonist: tropism assay

▪ If prior failure on INSTI-containing regimen, test for INSTI

resistance

Other considerations ▪ Prior treatment history should be obtained

M184V

M = Methionine

184 = the codon #

V = Valine

A mutation at codon #184 in

the gene Reverse Transcriptase

codes for a Valine residue

where normally a Methionine

residue is found.

M184V

• Emerging first in a non suppressive regimen that contain 3TC or FTC.

• Give rise to resistance to 3TC,FTC but :

• No clinical implications.

• They should be still used for partial viral suppression and to decrease replication.

• Increased affinity to AZT, D4T & TNF.

K65R & L74V

• With initial use of TNF, ABC, DDI.

• TNF : K65R

• DDI : L74V

• ABC : L74V > K65R

• K65 reduces viral replication (VR) by 30 folds.

• It also causes hyper-susceptibility to AZT.

NNRTI Mutatations

• K103N is most common one, followed by C181Y

• Remember: they lead to cross resistance to all NNRTIs.

Patient R48 year old with diagnosed 5 years ago.

Started on AZT, 3TC and efaverenz 2 years ago.

Noncompliant, lost to follow up.

VL:200,000 c/ml CD4: 125 cells/mm3

Genotype:

NRTI

M184V, K219R

NNRTI

K103N, V108I

PI

None

DHHS: Management of First-line Failure

DHHS Guidelines.

*If RAL or EVG resistance detected, DTG + boosted PI can be used if DTG susceptible.

Failing Regimen (+ NRTIs)

▪ Boosted PI: Enforce adherenceModify for convenience or toxicity

▪ NNRTI: Boosted PI + NRTIsBoosted PI + INSTI

▪ INSTI: Boosted PI + NRTIsBoosted PI + active INSTI*

EARNEST: Second-line LPV/RTV ± RAL or 2-3 NRTIs in PI-Naive Pts

• Randomized, open-label, multicenter phase III trial in sub-Saharan Africa

LPV/RTV + RAL

(n = 433)

LPV/RTV + 2-3 NRTIs*

(n = 426)

HIV-infected pts

> 12 yrs of age

with confirmed VF on

NNRTI + 2 NRTIs

and no prior PIs

(N = 1277)

Wk 96

LPV/RTV 400/100 mg and RAL 400 mg dosed

BID.

*New or recycled NRTIs chosen WITHOUT

genotype by clinician.

Wk 12

LPV/RTV Monotherapy

(n = 418)

LPV/RTV + RAL

(n = 418)

Paton NI, et al. N Engl J Med. 2014;371:234-247.

Stratified by study

center, CD4+ cell

count (< 200 vs ≥

200 cells/mm3)

EARNEST: Boosted PI + RAL Comparable to Boosted PI + NRTIs

• SECOND-LINE[3] and ACTG 5273[4,5] showed similar results

LPV/RTV + RAL

(n = 433)

LPV/RTV + 2/3

NRTIs

(n = 426)

LPV/RTV

monotherapy

(n = 418)

10

0

8

0

6

0

4

02

0

0

Pts

(%)

HIV-1 RNA < 50

copies/mL,

Wk 96[1]

7473

44

P < .001

HIV-1 RNA < 400

copies/mL Through

Wk 144[2]

LPV/RTV + NRTI(Number of Active

NRTIs)

Pts

(%

)

88

0 LPV/RTV

+ RAL

7781

85

61

1 2-3

LPV/RTV

Virologic failuere with first line regimen

-DTG plus two NRTIs (at least one of which is active) can be

an option after failure of a first-line, NNRTI-based therapy (

based on DAWWNNG trial) (AI).

-Bictegravir (BIC) may have activity that is similar to that of

DTG; however, there are currently no data to support its use.

Adapted from DHHS Guidelines, October 25, 2018

PI Resistance

• PIs have high genetic barrier that is why Detectable virus in the face of boosted PI is rarely due to mutations. It is rather due to non-compliance . options:

• stress on adherence and repeat VL in 4 weeks.

• Switch to another PI.

• Switch to another class

The Role of Maraviroc

Highly effective in experienced pat. With R5 virus ( motivate trial).

Requires screening with tropism assay,

50% of experienced pat. Not candidates for MVC due to D/M or X4 virus.

D/M or X4 virus can be missed if present at less than 10%

Not approved as first line in naïve patients.

Raltegravir Resistance

• From BENCHMARK 1 & 2

• Partial analysis from 41 raltegravir failure: 32 with integrase changes, 9 with no consistent changes from baseline.

• N155H and Q148K/R/H are the recognized pathways.

• Unfortunately, they carry cross resistance to other elvitigravir.

Dolutegravir

Current Status of INSTI Resistance in the US

Transmitted INSTI resistance remains rare and rates of on-treatment INSTI resistance continue to be low[1-3]

1. Hernandez AL, et al. CROI 2017. Abstract 478. 2. Davy T, et al. CROI 2017. Abstract 483.

3. Koullias Y, et al. CROI 2017. Abstract 493.

Study Key Findings

CDC National HIV

Surveillance

System[1]

▪ Prevalence of INSTI resistance for HIV

diagnoses through 2014:

65/14,468 (0.4%)

▪ Pre-ART prevalence of INSTI resistance (ie,

transmitted): 2/4631 (0.04%)

UNC CFAR HIV

Clinical Cohort[2]

▪ 2015 INSTI resistance prevalence in 685 pts

who began ART in 2007 or later: 1%

Modeling study[3]

▪ Assuming 0.1% rate of transmitted INSTI

resistance and $250 cost per test: pre-ART

INSTI resistance testing correlated with worse

outcomes, higher costs vs no test

DHHS: Management of ART Failure Second-line ARV Failure

Goal: fully suppressive ARV regimen If susceptible to boosted PI, regimen

can be similar to those for first-line failure

If not susceptible to boosted PI, new regimen should have a minimum of 2 (preferably 3) fully active drugs if possible◦ Susceptibility to drug predicted from

pt treatment history, prior and current resistance and tropism testing, MoA of novel drug class

Not recommended to add single agent to failing regimen due to risk of developing resistance to entire regimen

DHHS Guidelines.

Boosted PI + NRTIs

Boosted PI + active

INSTI

2 and preferably

3 fully active

drugs

Yes No

PI

Susceptible

DHHS: Treatment of Pts With MDR HIV for Whom Optimal Virologic Suppression Is Not

Possible

Goals: minimize toxicity, preserve immunologic function,delay clinical progression, minimize further resistance

◦ Reduction of HIV-1 RNA > 0.5 log10 copies/mL correlated withclinical benefit

◦ If resistant, rarely a reason to continue NNRTIs, ENF, EVG, or RAL:no evidence of clinical benefit; may promote further resistance,limit future treatment options

DHHS Guidelines.

Emerging Investigational Agents for Pts With MDR HIV

1. Lalezari JP, et al. Lancet HIV. 2015;2:e427-437. 2. Granados-Reyes ER, et al. HIV

Glasgow 2016. Abstract O335A. 3. ClinicalTrials.gov. NCT02362503. 4. Lewis S, et al. CROI

2017. Abstract 449LB.

5. Lin H-H, et al. CROI 2017. Abstract 438. 6. Lalezari J, et al. CROI 2017. Abstract 437.

Investigational

AgentPhase MoA

Fostemsavir[1-3] III

Prodrug; when metabolized

binds gp120 to prevent CD4+

cell attachment, entry

Ibalizumab[4,5] IIIHumanized anti-CD4 receptor

mAb

PRO 140[6] IIb/III Humanized anti-CCR5 mAb

TMB-301: Ibalizumab in Pretreated Pts Infected With Multidrug-

Resistant HIV• Ibalizumab: humanized mAb to CD4 receptor that blocks HIV entry into

CD4+ T-cells

– FDA breakthrough and orphan drug designations

• Single-arm, open-label phase III trial

– Primary endpoint: ≥ 0.5 log10 HIV-1 RNA decrease at Day 14

Lewis S, et al. CROI 2017. Abstract 449LB.

Pts with HIV-1 RNA

> 1000 copies/mL;

on ART ≥ 6 mos, on

stable ART ≥ 8 wks;

resistant to

≥ 1 ARV from 3

classes, sensitive to ≥

1 ARV for OBR

(N = 40)

Wk 25

Ibalizumab

2000 mg IV Day 7

(loading dose)

Continue Failing ART

Days 0-14

Ibalizumab

800 mg IV Day 21, Q2W

(maintenance dose)

Switch to OBR

Day 14

Primary Endpoint:

Day 14Control Period:

Day 0-7

TMB-301: Efficacy

Lewis S, et al. CROI 2017. Abstract 449LB.

Virologic Outcome

Ibalizum

ab +

OBR

Day 14

≥ 0.5 log10 HIV-1 RNA decrease,

%

83*

≥ 1.0 log10 HIV-1 RNA decrease,

%

60

Mean HIV-1 RNA decrease, log10 1.1

Wk 24

≥ 1.0 log10 HIV-1 RNA decrease,

%

55

≥ 2.0 log10 HIV-1 RNA decrease,

%

48

HIV-1 RNA < 50 copies/mL, % 43

HIV-1 RNA < 200 copies/mL, % 50

Mean HIV-1 RNA decrease from

BL, log10

1.6

*Primary endpoint; P < .0001 vs 3% at end of control period.

Outcome,

cells/mm3

Baseline CD4+ Cell

Count (cells/mm3)

< 50

(n =

17)

50-200

(n =

10)

> 200

(n =

13)

Mean baseline

CD4+ cell

count

12 109 363

Mean increase

in CD4+ cell

count at Wk 24

▪ Missing

equals failure

analysis

9 75 78

▪ Per protocol

analysis15† 75 81‡

†n = 7. ‡n = 10.

Take-Home Points

Primary resistance continue to occur, do GT test before HAART

For pts with virologic failure and potential MDR HIV, genotypic andphenotypic resistance testing results and treatment history shouldinform the construction of new ART regimens

For pts with confirmed MDR, the goal of a new regimen is aminimum of 2 (preferably 3) active drugs if possible

◦ For pts with resistance to currently available agents, refer to aspecialized center for expanded access program

◦ Investigational agents with novel MoAs may provide options forpts with MDR HIV Fostemsavir (gp120 binder; prevents CD4+ cellattachment), ibalizumab (anti-CD4 receptor mAb), PRO 140 (anti-CCR5mAb)

The Goal of Therapy

The goal of therapy is virologicsuppression to < 50 c/ml in allpatients.

DHHS & IAS- USA Guidelines