HIV Clinical Management:Antiretroviral Therapy and Drug Resistance

Judith S. Currier, MD, MSc

Professor of Medicine

University of California, Los Angeles

Disclosures:Research Grant from Theratechnologies to UCLA

Clinical Management Topics

• Initial Antiretroviral Therapy• Efficacy and Tolerability

• Resistance • Epidemiology

• Resistance Testing

• Second and Third Line ART

• Future priorities

ART Recommended for All People with HIV

ART recommended for early HIV infection[1,2]

– DHHS and WHO guidance recommend ART for all HIV-infected pts worldwide, regardless of CD4+ cell count

ART recommended for pregnant with early HIV infection[1]

1. DHHS Guidelines. January 2016. 2. WHO. September 2015.

Number of people receiving antiretroviral treatment

Source: UNAIDS/WHO estimates.The red shading shows future targets.

Antiretroviral Therapy : What to Start in 2017

Antiretroviral Therapy : What to Start in 2017

Efavirenz based ART as First Line

• Advantages

• Single tablet regimens available at low cost

• Over 15 million person years of treatment experience with efavirenz 600 mg/day

• Generally well tolerated

• Safely used in pregnancy and for patients with TB

• Challenges

• CNS side effects are common

• Drug interactions

• Low barrier to resistance

Alternative First Line ART

• Lower dose EFV 400 mg

• Better tolerated• Lower cost

• Dolutegravir

• Superior virologic outcomes compared to EFV • Fewer drug Interactions• Very low risk of resistance at failure: no cases of resistance

in first line clinical trials with DTG• Limited data in children, pregnant women and TB-

coinfection• Will Immune Reconstitution Inflammatory Syndrome (IRIS)

be a problem?

Using INSTI may enhance the risk of IRISART with INSTI N=398

ART without INSTI N=1889

Pre-ART CD4 cell count

34 84

Pre-ART Viral Load 5.3 5.2

IRIS Cases, N (%) 12 (3.0) 29 (1.5)

M. tuberculosis 5 (42%) 7 (58%)

M. avium 2 (20%) 8 (80%)

Progressive Multifocal Leukoencephalopathy

1 (16.7%) 5 (83.3%)

CMV 2 (40%) 3 (60%)

Kaposi sarcoma 2 (50%) 2 (50%)

Toxoplasmosis 0 2

2287 Patients Multi-center cohort study in France IRIS events requiring hospitalization, mainly related to mycobacterial infections, were rare but twice as frequent among patients with CD4 cells below 200/mm3 who initiated INSTI-based ART regimen compared those without an INSTI

Neuropsychiatric AEs in Dolutegravir

• Retrospective analysis on 2260 HIV+ patients in France

• Median age 50

• CD4 591

• DTG discontinuation for Neuropyschiatric (NP)-AEs was 5.4%

• Irritability and sleep disturbances were the most frequently observed NP-AEs

• >60 years old, female sex, and BMI were significantly associated with NP-Aesoccurrences.

Ongoing International Trials with DTG, EFV and EFV 400

• Pregnant women• Dolphin- 1, Dophin-2, VESTED (DTG/FTC/TAF vs DTG/TDF/FTC vs EFV/TDF/FTC)

• TB Coinfection• EFV 400 + rifampicin• EFV +NRTI vs DTG + 2 NRT in TB• TAF + rifampin

• Treatment Naïve• ADVANCE (South Africa) DTG/TAF/FTC vs DTG/TDF/FTC vs EFV/TDF/FTC• NAMSAL (Cameroun) DTG/3TC/TDF vs EFV400/3TC/TDF/

• Second Line• DAWNING 2NRTI +DTG s 2NRTI + PI/r• D2EFT DTG/DRV/r vs 2NRTI + DRV/r

Vitoria, Ford, Clayden, Pozniak and Hill. Curr Opin HIV AIDS 2017

HIV DRUG RESISTANCE

Image from Scientific American, 1998

The presence of transmitted drug resistance to NNRTI or NRT increases risk of virologic failure on first line ART with NNRTI’s

HIV Drug Resistance : Context is Important

• Transmitted resistance in treatment naïve

• Resistance after first line failure• Duration of failure and availability of VL monitoring

• Resistance after second line

HIVDR in ARV-naïve Individuals

East Africa Southern Africa

West & Central Africa Latin America & Caribbean

Pre-Rx Drug Resistancein Children in SSA

RV 329: African Cohort Study (AFRICOS)

• Prospective observational HIV-focused cohort executed by US Military HIV Research Program with PEPFAR and Department of Defense researchsupport

• Enrolling adults aged 18+ at 11 HIV

clinic sites in 4 countries

• Current enrollment over 2600 HIV

infected and 500 HIV uninfected

participants with 6 monthly visits

• HIV outcomes measured: CD4, viral load,

genotype resistance testing at baseline

and virologic failure

• Serum, plasma and cells stored

Slide credit: Julie Ake

Drug Resistance – ART Naïve ParticipantsUganda

n=92 (%)

Kenya

n=35 (%)

Tanzania

n=59 (%)

Nigeria

n=35 (%)

Total

n=221 (%)

Any SDRM 7 (8) 2 (6) 7 (12) 6 (17) 22 (10)

Major NRTI Resistance 2 (2) 0 (0) 1 (2) 4 (11) 7 (3)

L74V 2 (2) 0 (0) 1 (2) 1 (3) 4 (2)

M41L 0 (0) 0 (0) 0 (0) 3 (9) 3 (1)

M184V/I 0 (0) 0 (0) 0 (0) 1 (3) 1 (0.5)

Major NNRTI Resistance 3 (3) 2 (6) 5 (8) 1 (3) 11 (5)

K103N 3 (3) 2 (6) 4 (7) 0 (0) 9 (4)

Y181C 1 (1) 0 (0) 1 (2) 0 (0) 2 (1)

G190A 0 (0) 0 (0) 0 (0) 1 (3) 1 (0.5)

Major PI Resistance 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Impact of HIVDR between 2016 and 2030 in sub-Saharan Africa (Low/Mid-Income countries)

AIDS Deaths New Infections ART Costs

With HIVDR (fast track projections) 5.6 million 5.1 million $ 83 billion

Current level of PDR < 10%Amount attributable to HIVDR

710,000 (13%) 380,000 (7%) $ 5.0 billion (6%)

Current level of PDR ≥ 10%Amount (%) attributable to HIVDR

890,000 (16%) 450,000 (9%) $ 6.5 billion (8%)

J Infect Dis. 2017 Feb 17

Resistance after First Line ART

Countries contributing data to resistance analysis and HIV-1 subtype distribution

1926 individuals from 36 countriesAdapted from Lancet Infect Dis 2016; 16: 565–75

TDF and NNRTI resistance after first line failure of TDF containing ART

CD4 < 100 risk strongest factor for TDF Resistance

Hosseinipour, M et al. JAIDS 2017 1;75 Suppl 2:S149-S155

HIV Drug Resistance in Option B + Malawi

• Prospective study of 1269 post-partum women randomized to different strategies for promoting uptake and retention of Option B+

• At 6 months follow-up• 75 % retained in care

• Of those retained 88 % had HIV RNA obtained and 84% were < 1000 copies ml

• Among the 55 with HIV RNA > 1000; 19(35%) had HIV drug resistance

Drug Resistance – ART Experienced Participants

Uganda

n=10 (%)

Kenya

n=21 (%)

Tanzania

n=17 (%)

Nigeria

n=17 (%)

Total

n=65 (%)

Major NRTI Resistance 2 (20) 11 (52) 10 (59) 9 (53) 32 (49)

M184V/I 2 (20%) 11 (52) 10 (59) 9 (53) 32 (49)

K70R 0 (0) 3 (14) 5 (29) 2 (12) 10 (15)

D67N 0 (0) 2 (10) 4 (24) 3 (18) 9 (14)

Major NNRTI

Resistance

3 (30) 15 (71) 14 (82) 13 (76) 45 (69)

K103N 1 (10) 7 (33) 7 (41) 10 (59) 25 (38)

Y181C 0 (0) 5 (24) 5 (29) 3 (18) 13 (20)

G190A 2 (20) 4 (19) 2 (12) 2 (12) 10 (15)

V106A/M 0 (0) 1 (5) 4 (24) 0 (0) 5 (8)

Major PI Resistance 0 (0) 0 (0) 0 (0) 1 (6) 1 (2)

High Prevalence of HIV DR among previously unmonitored patients with Virologic Failure in Malawi

• Examined rates of HIV Drug Resistance among 1498 patients in 5 district hospital programs on first line ART

• Viral load obtained if on treatment for at least 6 months, 24 months or longer or with clinical failure

• If VL > 5000 copies, adherence counseling done with repeat VL 3 months• Sent samples for resistance testing if confirmed VL 88 (5.8%) had VF

• Among these patients with resistance testing (n=61) 95% had resistance to NRTI or NNRTI

• 50% had high level resistance to NRTI and 50% high level NNRTI• Longer duration of ART associated with higher rates of resistance

• Patients in care for longer time with VL should be prioritized to shift to second line ART

Rustein SE IDWeek2016;Abstract 1551.

Resistance at first failure and response to second line ART

• Second line ART after NNRTI first line

• Three major studies all compared LPV/r + 2 NRTI with RAL + LPV/r

• SECOND LINE1 (2-3 NRTI +LPV/r vs LPV/r + RAL)

• EARNEST 2 (2-3 NRTI + LPV/r vs LPV/r + RAL vs LPV/r monotherapy

• SELECT (ACTG)3 (2 NRTI + LPV/r vs LPV/r + RAL )

• All 3 studies demonstrated non-inferiority of LPV/r + NRTI , no clear advantage of LPV/r + RAL

• Resistance testing was done in retrospect

1. Boyd M et al Lancet. 2013 Jun 15;381(9883):2091-9. 2. Paton N, et al N Engl J Med 2014; 371:234-247 3. LaRosa A, CROI 2017

HIV Drug Resistance after First Line Failure in EARNESTMalawi, Uganda, Kenya and Zimbabwe

Kityo C, et al JAIDS June 2017 Suppl

• 787 adults failing first line NNRTI treatment- median duration 4 years

• Viral subtype distribution• A1 (40%; Uganda and Kenya)

• C (31%; Zimbabwe and Malawi)

• D (25%; Uganda and Kenya)

• DRM more common in subtype C

• Tenofovir resistance similar by subtype

• Subtype C resistance to ZDV, ABC, etravirine and ripivirine more common implications for second and third line

Paradox: Impact of Baseline Resistance on Risk of Virologic Failure• No differences between arms, or after adjustment for baseline HIV-1 RNA,

Wk 4 adherence, previous TDF use, country[1]

• ACTG 5273 overall results consistent with EARNEST, SECOND-LINE trials[2,3]

1. La Rosa AM, et al. CROI 2016. Abstract 30.

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

3. Amin J, et al. PLoS One. 2015;10:e0118228.

Baseline NRTI Resistance HR for VF in Both Arms

(95% CI)

P Value

K65R, ≥ 3 TAMs, Q151M or 69 ins/del

Yes vs no (ref)0.49 (0.31-0.76) .001

IAS NRTI mutations

≥ 3 vs < 3 (ref)0.45 (0.30-0.70) < .001

K65R and/or M184V/I

No K65R but M184V/I vs no M184V/1 (ref)

K65R and M184V/I vs no M184V/1 (ref)

0.41 (0.25-0.67)

0.19 (0.08-0.44)

< .001

Slide credit: clinicaloptions.com

Resistance Testing and Clinical Practice: More Questions than Answers• Identifying NNRTI resistance could inform the selection of first line

ART• How should surveillance data be used to inform local guidelines?

• Will first line DTG overcome this problem for first line?• Cost effectiveness analyses suggest DTG cost effective when NNRTI resistance > 10% (Hill

Abs 112, CROI 2017)

• Value of Resistance Testing in Third Line• A5288/MULTI-OCTAVE: Management Using Latest Technologies to Optimize

Combination Therapy evaluating use of resistance testing for 3rd line – due to report end of 2017

http://www.who.int/hiv/drugresistance/HIVDR_OverviewGAP_Doherty.pdf?ua=1

ART Resistance Guidelines GroupMeeting March 2017

PreventionSurveillanceResearchLaboratory CapacityGovernance

Summary

• Clinical Management of ART is evolving • Optimal uniform first line global regimen remains a goal- we are not there yet

• Earlier treatment expansion needs to be coupled with focus on long term adherence

• Newer treatment regimens offer promise for less resistance and toxicity, cost effectiveness studies are key to guide policy

• Viral load monitoring scale up critical for earlier detection of VF and prevention of resistance

• Clinical use of resistance testing may be most effective for third line ART

US MHRP

Zikomo