HIV 2016: Recent Clinical Breakthroughs and What’s on the Horizon

Disclosures: grant support from EBSCO, Gilead, Roche, Merck, Viiv

Thanks to Drs. Jared Baeten, Katie Bar, Alvaro Borges, Heather Bradley, Joe Eron, Jon Li, Shahin Lockman, James Whitney and Neha Patel for assistance with slides

Rajesh T. Gandhi, M.D.Massachusetts General Hospital

Luke Jerram

Learning Objectives

Following completion of this session, learners

will be better able to:

• identify recent breakthroughs in preventing

HIV

• identify recent advances in the care of HIV-

infected patients.

• evaluate ongoing efforts to improve future care of HIV-infected patients.

Case

• 40 yo F, originally from Haiti, admitted to the hospital with worsening odynophagia

• HIV antibody test is positive. CD4 count 75. HIV RNA 250,000 copies/mL

• She asks you 3 questions:

– “How could this have been prevented?

– “How should I be treated?”

– “Can my HIV be cured?”

HIV 2016: Where are we now, where do we need to be?

• Breakthroughs in Prevention

• Breakthroughs in Treatment

• What’s on the Horizon – Can we cure HIV?

HIV: At Home and Around the World

New infections in 2014: 2 million

US: 1.2 million living with HIV Globally: 36.9 million living with HIV

New infections in 2014: 45,000

HIV Prevention: Bending the Epidemic Curve

• Who’s at Risk

• Getting to 90:90:90

• Pre-exposure prophylaxis (PrEP)

• Women-controlled prevention: Dapivirine Vaginal Ring

“How could this have been prevented?”

Estimated Lifetime Risk of HIV in US

Hess et al, CROI 2016, # 52 http://www.cdc.gov/nchhstp/newsroom/docs/factsheets/lifetime-risk-hiv-dx-us.pdf

• CDC analysis

• Lifetime risk: 1 in 99

• Marked discrepancies by race, risk group and geography

DC: 1 in 13; GA: 1 in 51; CT: 1 in 139; MA: 1 in 121; ND 1 in 670

Ending the Epidemic with ART?

1. Cohen MS, et al. N Engl J Med 2011;10.1056. 2. Cohen MS, et al. IAS 2015, MOAC0101LB. 3. UNAIDS, 2014

• Treatment and virologic suppression markedly reduce transmission1,2 (“Treatment as prevention”)

• Modeling suggests that treating a high proportion of infected patients could end the epidemic by 20303

• UNAIDS Treatment Targets:

=73% suppressed

68%

62% 61%59%

52% 52%

40%

35%32%

30% 30%

9%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Switzerland<200

Australia<400

UnitedKingdom

<200

Denmark<500

Rwanda<40

France <50 Brazil<1000

BritishColumbia(Canada)

<50

SubSaharan

Africa <400to <40

Cuba USA <200 Russia<1000

UNAIDS Target: 73% of all HIV+ people achieving viral suppression

(*SSA = Regional average From 30 countries)Adapted from Levi J, et al. IAS 2015. MOAD0102.

Percentage of HIV+ People with HIV RNA Suppression

Reducing HIV Transmissions in US: Expansion of Testing, Retention and Treatment

• >90% of transmissions are from undiagnosed HIV-infected patients or from those diagnosed but not retained in care

• CDC projects 265,000 HIV infections in next 5 years at current testing and treatment rates

• Achieving National HIV/AIDS Strategy goals (85% linked, 90% retained, 80% suppressed)avert >185,000 infections

• Need to:

– Expand testing (eg, inpatient and outpatient order sets)

– Improve retention: innovative studies (eg Project HOPE)

– Accelerate PrEP roll-out

Skarbinski et al, JAMA Int Med, 2015; http://www.cdc.gov/nchhstp/newsroom/images/2016 croi_four_scenarios_graph.jpg

iPrEX MSM and transgender women in 6 countries (n=2499)

44% reduction in acquisition

Partners PrEP

Serodiscordant couples in Africa (n=4747)

67-75% reduction inacquisition

TDF2 Heterosexual adults in Africa (n=1219)

62% reduction in acquisition

FEM-PrEP Women in Africa (n=2120) No HIV risk reduction

VOICE Women in Africa (n=5029) No HIV risk reduction

PROUD High-risk MSM in UK (n=545) 86% reduction in acquisition

TDF2-OLE Men, women in Africa (n=229) 0 infections

Kaiser People (mostly MSM) in San Francisco (n=657)

0 infections

Randomized trials of TDF/FTC or TDF PrEP

Effectiveness even higher in real-world settings

PrEP 2016

<50% ever took study

drug

Limitations of TDF/FTC PrEP

• Importance of adherence with oral dosing

• Potential for renal and bone toxicity, especially with higher exposure (e.g. daily dosing)

Greater decline in eGFR with higher drug exposure

Decline in bone mineral density after starting TDF/FTC is reversible

Gandhi M et al, CROI 2016, #883; Grant R et al, CROI 2016, #48LB

New PrEP?

• Improve adherence:

– Vaginal rings

• Decrease toxicity:

– Maraviroc?

– Tenofovir alafenamide (TAF)?

Women-controlled Prevention: Dapivirine Vaginal Ring

• High rate of HIV acquisition among women in Africa highlights need for women-controlled long-acting agents

• Vaginal rings containing hormones are licensed for contraception

• Dapivirine, an NNRTI, in vaginal ring studied in two phase 3 randomized trials (ASPIRE and RING) in Africa

• Women inserted ring containing dapivirine or placebo monthly

Baeten et al, CROI 2016, #109LB and NEJM, 2016. Nel et al, CROI 2016, #110 LB

• In ASPIRE, HIV incidence 27% lower in dapivirine gpthan in placebo group

• >21 yo: 56% lower rate

• ≤ 21 yo, no protection (reduced adherence)

• Similar results in RING trial

• Demo projects needed to assess effectiveness in open-label settings

Dapivirine Vaginal Ring Reduces HIV Acquisition

Age 18-21 yr Age 22-26 yr Age 27-45 yr

Baeten et al, CROI 2016, #109LB and NEJM, 2016. Nel et al, CROI 2016, #110 LB

• Maraviroc: alone or with FTC or TDF compared to TDF/FTC: all 5 incident HIV infections occurred in MVC groups (drug level low or absent in several cases)

Alternative Agents for PrEP: Not Yet Ready for Prime Time

Gulick R et al, CROI 2016, #103. Massud CROI 2016 #107. Garrett CROI 2016 #102LB

• Tenofovir alafenamide (TAF):

– Lower plasma tenofovir (TFV) levels than with TDF less renal, bone toxicity

– Protected macaques from infection

but:

– In women who received a single dose, >50% had undetectable TFV-DP in vaginal or rectal tissue

• Where are we now?

– Multiple effective methods of preventing HIV: condoms, male circumcision, treatment as prevention, oral PrEP

HIV Prevention 2016

• Where do we need to be?

– Diagnose and treat many more people (95-95-95 by 2030)

– Make PrEP easy to adhere to, accessible and controlled by those who most need it: long-acting formulations, alternative agents

Breakthroughs in Treatment

• State of the ART, 2016

– When to start

– What to start

– Improving ART

“How should I be treated”?

Where Do We Come From? What Are We? Where Are We

Going?

– Paul Gauguin

When to START?

• START enrolled 4685 pts from 35 countries

• Primary endpoint: serious AIDS-related event, serious non–AIDS-related event, or death

• May 2015: DSMB recommended offering ART to all participants

• Median age: 36 yrs; mean follow-up 3 yrs.

• Median baseline CD4 count 651. Deferred group: median CD4 count at ART initiation, 408

Insight START Study Group, NEJM, 2015

HIV-infected adults

CD4 count >500

Immediate ART (n=2326)

Deferred ART (n=2359)(CD4 Declined to <350 or AIDS-related event)

Lundgren J, et al. 8th IAS Conference. Vancouver, 2015. Abstract MOSY0301.The INSIGHT START Study Group. N Engl J Med. 2015;July 20. Lifson A et al, CROI 2016, #475; Borges et al, CROI 2016, #160

0

20

40

60

80

100

Nu

mb

er

of

Even

ts

AIDS-Related

Non-AIDS Related

Components(Serious Events)

CompositeEndpoint

96Deferred ART (n=2359)

Immediate ART (n=2326)

42

50

14

47

29

Number of Serious Events

57%Reduction(P<0.001)

72%Reduction(P<0.001)

39%Reduction(P=0.04)

• TB, KS, lymphoma —most common AIDS-related events — all less frequent in immediate-ART group

• Cancer rates (combining AIDS/non-AIDS) lower in immediate-ART group

• Decreased bacterial infections, improved quality of life in immediate ART group

Immediate ART Prevents AIDS- and Non-AIDS Related Events

US DHHS Guidelines, January 2011.

ART recommended for all HIV+ individuals, regardless of CD4 cell count

AI: strong recommendation, data from randomized clinical trials

CD4 Cell Count Recommendation

≤ 350

350-500

>500

AI

AI

AI

“When should I start treatment?”You should start now!

WHO on Sept 30, 2015: “Treat-all”

Updated July 28, 2015

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Updated July 2015

First-line Treatment

Integrase inhibitor:

Raltegravir, Elvitegravir/cobi*, Dolutegravir**

or

Two NRTIs

TDF/FTC

or

TAF/FTC

or

Abacavir/3TCBoosted PI:

Ritonavir-boosted darunavir

Plus

*Coformulated with TDF/FTC and TAF/FTC**Coformulated with ABC/3TC

TDF: tenofovir disoproxil fumarateTAF: tenofovir alafenamide

“How should I be treated?”

Tenofovir alafenamide (TAF)

• TAF: pro-drug of tenofovir that concentrates in cells, converted to tenofovir (TFV)

• TAF: 90% lower plasma TFV levels compared to TDF (tenofovir disoproxil fumarate)

• TAF compared to TDF for initial therapy:

n=1733

Sax P et al, Lancet, 2015

TAF vs. TDFH

IV-1

RN

A <

50

c/m

L,

%

92

4 4

90

4 6

0

20

40

60

80

100

Success Failure No Data

• Virologic efficacy: E/C/F/TAF non-inferior to E/C/F/TDF

• TAF associated with:

− Smaller decrease in bone mineral density (BMD)

− Smaller decrease in eGFR

− Less proteinuria

− However, greater increases in cholesterol, LDL, HDL, TGs (identical changes in TC:HDL)

• Similar results in switch studies

• TAF approved down to eGFR > 30

• TAF active against HBV

E/C/F/TAF

E/C/F/TDF

Sax P et al, Lancet, 2015. Gallant J, et al. 8th IAS Conference, 2015. WELBPE13. Gallant J et al, CROI 2016, #29

Elvitegravir/c/FTC/TAF – Nov. 2015Rilpivirine/FTC/TAF – Mar. 2016

FTC/TAF – April 2016Darunavir/c/FTC/TAF – phase III

Individualizing Treatment

• Reducing pill burden: many regimens are 1-2 pills/day

• Addressing comorbidities:

– Kidney disease: avoid TDF; favor ABC or TAF

– Osteoporosis: avoid TDF; favor ABC or TAF

– CV disease: prefer TDF or TAF

• Avoiding drug interactions:

– Avoid PI- or cobi-containing regimen if patient on CYP3A4-metabolized medication, e.g. inhaled or injectable steroids

“How should I be treated”

Hyle E et al, JAIDS, 2013

• Cabotegravir (CBG) and rilpivirine(RPV): nanosuspensionformulations; half-lives of months

• VL <50 at wk 32

– q 8 wk IM: 95%

– q 4 wk IM: 94%

– Oral: 91%

• 1 virologic failure in IM arm (no resistance; no detectable RPV)

• Injection site reactions mild (median 3 days)

• Patient satisfaction high

Long-acting Injectable Cabotegravir plus RilpivirineMaintains Virologic Suppression

Spreen, JAIDS 2014; Jackson, Clin Pharmacol Ther 2014; Margolis DA et al, CROI 2016, #31LB; Markowitz M et al, CROI 2016, 106.

Latte-2

(n=309)

Wk 48 analyses will inform selection of dose for phase III

studies.

n=115; 2 x 2 ml IG

n=115; 2 x 3 ml IG

n=56

• Where are we now?

– Multiple effective treatment options: Individualize therapy based on patient characteristics

• Where do we need to be?

– Many infected people not receiving effective therapy

• Stigma, substance use, mental illness, poor access to care

• Need strategies to improve adherence – tear down barriers to care. Injectables? Implants? Vectored delivery?

– Drugs that can be used safely and effectively for decades

• Reduce renal, hepatic, bone, and neurologic toxicity

• Minimal or no drug interactions (important as patients age)

– New classes that overcome drug resistance as it emerges

HIV Treatment 2016

On the Horizon – Can We Cure HIV?

“Can my HIV be cured?”

Why Should We Try to Cure HIV?

• Although life expectancy has improved, HIV+ people don’t live as long as HIV-negative people -- perhaps because of persistent inflammation, immune activation and associated end-organ diseases (CV disease, stroke, neurocognitive dysfunction, and other complications)

• Cost, side effects, impact on quality of life of indefinite ART

• Need to maintain high level of adherence to ART to prevent drug-resistant virus

• Stigma, discrimination, fear of transmission, isolation

Adapted from slide from Joe Eron, MD

What do we need to do to cure HIV?Reducing the HIV Reservoir

Latently infected cells in patients on

suppressive ART are “invisible” to the

immune system.

Goals of current studies:

1. Develop agents to reverse latency and

induce HIV expression to make cells

vulnerable to clearance and

2. Develop interventions that enhance

immune responses to clear infected cells

Strategy 1: Reverse Latency

• Latent HIV is transcriptionally silent. One mechanism may be histone deacetylation“closed” chromatin

• Histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, panobinostat) induce viral expression1-5 but have little effect on HIV reservoir inducing HIV expression alone may not kill infected cells6

VOR1

VOR2

VOR3

VOR6

VOR7

VOR8

VOR11

0

20

40

60

200

400

600

800

Re

lativ

e H

IV-1

gag

RN

A c

op

ies

Baseline ART

VOR 400 mg

Single-dose vorinostatinduces HIV expression

Mean 4.8-fold

induction (range

1.5 -10 fold)

Archin NM, et al. Nature. 20121

Richman DD, et al. Science. 2009

2JH Elliott et al, PLoS Pathogens, 2014; 3Rasmussen T et al, Lancet HIV, 2014; 4Sogaard O et al, PLoS Pathogens, 2014. 5Leth S et al, CROI 2016, #26LB. 6Shan L et al, Immunity, 2012

We need to understand how to more effectively reverse HIV

latency. May need to combine latency

reactivating agents with immune enhancing interventions.

• Toll-like receptor-7 (TLR-7)

– Increases immune responses

– Induces HIV expression

• TLR-7 agonist in SIV-infected macaques on suppressive ART:

TLR-7 Agonist

Whitney J et al, CROI 2016, #95LB.

2 of 9 animals did not have viral rebound for > 3 m. after ART stopped

V1

V2 0 24 48 72 168 0 24 48 72 168 0 24 48 72 168 0 24 48 72 168 0 24 48 72 168 0 24 48 72 168 0 24 48 72 168 0 24 48 72 168 0 24 48 72 168 0 24 48 72 168

Vehicle

Induction of SIV viremia

No s

timula

tion

Pre-T

LR7

Post

10t

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Post

19t

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Pre-T

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Post

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h101

102

103

104

105

106

107

162-09

305-10 280-10

288-10

344-10 293-09

295-10

304-10

177-10

341-10

412-10

ConA

Placebo GS-986 (0.1mg/kg) GS-9620 (0.05mg/kg) GS-9620 (0.15mg/kg)

PBMC LN PBMC LN PBMC LN PBMC LN

ConA ConA ConA

Reduction in viral reservoir

• Potent and broad neutralization of a large variety of HIV isolates.

• Can be engineered to increase half-life or improve immune function

– Bispecific antibodies, DARTs

• Entering clinical trials for prevention, treatment, reservoir reduction.

41 6 82 3

ATI Weeks

VRC01 40 mg/kg

5 7

Variable duration until HIV VL 1000 copies/ml

OR CD4 < 350

Screening Entry

ART

1ary

endpoint

HIV <50 for 6 monthsCD4 > 400

STEP 1: VRC01 administration and

Analytical Treatment Interruption

Study Weeks0 4 6 82 3 7

9

1 5

Pre-Entry

Rectal Biopsy/Leukopheresis

HIV viral load/PKSafety (CBC, CD4, CMP)

Viral Rebound

0

-1

Caskey M et al, Nature 2015; Lynch R et al, Sci Transl Med 2015; Mascola JR, CROI 2016, plenary. Bar K et al, CROI 2016, #32LB. Chun TW et al, CROI 2016, #311LB.

ACTG A5340

May need to combine antibodies that mediate killing of infected cells with latency reversing agents that induce HIV expression

Strategy 2: Improve Killing of Infected Cells:Broadly neutralizing antibodies (bNAbs)

Can we cure HIV?

“It's tough to make predictions, especially about the future”

Can we cure HIV?

• Thus far, HIV has been cured only under extraordinary circumstances HIV cure remains an aspirational goal.

• Studies are underway to test new ways of reversing latency and clearing infected cells. Combination approaches are likely to be needed.

• Increased knowledge of mechanisms of HIV persistence, how to accurately measure the HIV reservoir and how to reduce the reservoir are needed if we are to cure HIV.

• Given safety of antiretroviral therapy and uncertainties regarding risks of new interventions, cure studies must adhere to the highest scientific and ethical standards.

Bringing it All Back Home

• HIV transmission rates remain unacceptably high at home and around the world: expansion of testing, treatment, and PrEP needed to bend the epidemic curve

• Current PrEP is effective but has limitations (adherence challenges, toxicities). New prevention methods, including vaginal rings, long-acting injectables, and alternative agents under development

• ART continues to improve, with less toxic agents and (hopefully) long-acting options

• New approaches to prevent, treat and, perhaps, cure HIV continue to advance

World AIDS Day, 2013: . . . the United States should be at the forefront of new discoveries into how to put HIV into long-term remission without requiring lifelong therapies -- or, better yet, to eliminate it completely.

Patient: One day I’d love to say, “I used to have HIV.”