Future Directions in HIV Clinical Research

Eric S. Daar, M.D.Chief, Division of HIV MedicineHarbor-UCLA Medical Center

Professor of MedicineDavid Geffen School of Medicine at

UCLA

Overview

• Diagnosis

• Prevention

• Treatment

• Cure research

Diagnosis

Infected and UnawareIn

cid

ence

(%

)

Diagnosed Linked

to Care

Retained

In Care

Prescribed

ART

Viral

Suppression

85%

70%

36%

26%

41%

CDC and Prevention National HIV Surveillance System1

1. Hall HI, et al. 19th IAC. Washington, DC, 2012. Abstract FrLBX05.

2. Marks et al. AIDS 2006; 20:1447

n=1,148,200 HIV-infected persons, 18% of whom are unaware of their infection.

Females (n=279,200)

Males (n=869,000)81%

65%

35% 32%25%

~25% Unaware of Infxn

~75% Aware of Infxn ~46%

NewInfections

~54% New

Infections

New Sexual InfectionsPeople Living with HIV

Accounting for:

Transmission Risk2

Revised CDC Recommendations for HIV Testing in Healthcare Settings

• Routine testing all 13 to 64 years in healthcare settings– Not based on patient risk

• Opt-out testing • No separate consent for HIV• Pretest counseling not

required• Repeat HIV testing left to

discretion of provider– Based on patient risk

Branson BM, et al. MMWR Recomm Rep. 2006;55(RR-14):1-17.

Rapid Home HIV Testing(Approved July 2012)

Window Period and HIV Infection

Efficiency of HIV Transmission

Cohen MS, et al. JID 2005; 191:1391-3

Potential threshold for transmission

VL with intervention (e.g. ARVs)

VL in semen without ARVs

4th Generation Antigen/Antibody

Proposed Testing Algorithm

CDC. MMWR 2014

Future Directions for Diagnosis

• Expand testing

• Target high risk populations

• Identify early infection

• Making diagnosis is just the beginning

Prevention

Total: 35.0 million [33.2 million – 37.2 million]

Middle East & North Africa

230 000[160 000 – 330 000]Sub-Saharan Africa

24.7 million[23.5 million – 26.1 million]

Eastern Europe & Central Asia

1.1 million [980 000– 1.3 million]

Asia and the Pacific

4.8 million[4.1 million – 5.5 million]

North America and Western and Central Europe

2.3 million [2.0 million – 3.0 million]

Latin America

1.6 million[1.4 million – 2.1 million]

Caribbean

250 000[230 000 – 280 000]

Adults and children estimated to be living with HIV2013

Adults and Children Estimated to be Living with HIV- 2013

Estimated number of adults and children

newly infected with HIV2013

Middle East & North Africa

25 000[14 000 – 41 000]Sub-Saharan Africa

1.5 million[1.3 million – 1.6 million]

Eastern Europe & Central Asia

110 000 [86 000 – 130 000]

Latin America

94 000[71 000 – 170 000]

Caribbean

12 000[9400 – 14 000]

Total: 2.1 million [1.9 million – 2.4 million]

Asia and the Pacific

350 000[250 000 – 510 000]

North America and Western and Central Europe

88 000 [44 000 – 160 000]

Estimated Number of Adults and Children Newly Infected with HIV- 2013

Estimated New Infection in U.S. (2010)

Estimated total= 47,500

Preventing HIV Transmission

Scienceexpress, July 19th 2010.18th IAC 2010, Vienna, Austria, Abst. TUS505

Scienceexpress, July 19th 2010.

(N=444)

(N=445)

High adherers (>80%) effectiveness = 54%

Cu

mu

lati

ve P

rob

abili

ty o

f H

IV In

fect

ion

Weeks

N=64

N=36

Risk Reduction 44% (95% CI: 15, 63)

P=0.005

Grant R. et al. NEJM 2010, ePub ahead of press.

iPrEx Study (n=2499)

iPrEx Protection and Adherence

Overall >90% Adherence

Detectable Drug Levels

Grant R. et al. NEJM 2010, ePub ahead of press.

Efficacy (95% CI)

Conflicting Results with Oral PrEP Trials

0 10 20 30 40 50 60 70 80 90 100%

TDF for young heterosexuals

(TDF-2)63% (22; 83)

FTC/TDF for HIV discordant couples

(Partners PrEP)

75% (55; 87)

Modified from: Abdool Karim SS. Lancet 2013; 381(9883):2060-2.

TDF/FTC for MSM

and TW

(iPrEx)

44% (15; 63)

TDF/FTC for injecting drug users

(Bangkok TDF)49% (10; 72)

TDF for HIV discordant couples

(Partners PrEP)

67% (44; 81)

TDF/FTC for

women

(FEM-PrEP)

6% (-52; 41)

TDF for

women

(VOICE)

-49% (-129; 3)

TDF/FTC for

women

(VOICE)

-4% (-49; 27)

-70 -60 -50 40 -30 -20 -10

HPTN 052: Treatment as Prevention

Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011 Jul 18. [Epub ahead of print]

Immediate ART Initiate ART at CD4+ cell count 350-550 cells/mm3

(n = 886 couples)

Delayed ARTInitiate ART at CD4+ cell count ≤ 250 cells/mm3*

(n = 877 couples)

HIV-infected, sexually active serodiscordant

couples; CD4+ cell count of the infected partner:

350-550 cells/mm3

(N = 1763 couples)

*Based on 2 consecutive values ≤ 250 cells/mm3.

96% reduction in risk of transmission from those on treatment

Future Directions for Prevention

• Expand testing and early diagnosis

• Optimize treatment as prevention strategies– Linkage and retention into care– Adherence with therapy

• Refine PrEP strategies– Microbicide (e.g. dosing frequency, long acting forms)– Systemic (adherence interventions, dosing, long acting

therapy)

• Vaccine research

Treatment

Source: UNAIDS / Lohse et al / Hoog et al / May et al / Hogg et al

Projected Impact of ART on Survival of a 20-yo in a High Income Country

When to Start Treatment

Clinical CategoryCD4 Count (cells/mm3)

HIV RNA(copies/mL)

2014DHHS

Guidelines

2014IAS-USA

Guidelines

AIDS-defining illness or severe symptoms

Any value Any value Treat

Asymptomatic <500 Any value Treat

>500 Any value Treat

Pregnant women Any value Any value Treat

HIV-associated nephropathy

Any value Any value Treat

HIV/HBV coinfection when HBV treatment is indicated

Any value Any value Treat

DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision March 27, 2012; Thompson MA, et al. JAMA. 2012;308:387-402.

*Unless elite controller (HIV RNA <50 copies/mL) or has stable CD4 cell count and low-level viremia in absence of therapy.The IAS-USA guidelines also recommends initiating antiretroviral therapy in HIV-infected patients with active hepatitis C virus infection, active or high risk for cardiovascular disease, and symptomatic primary HIV infection.

HIV replication cycle and sites of drug activity

Capsidproteinsand viral

RNA

CD4Receptor

Viral RNA

New HIVparticles

Protease

Attachment Uncoating ReverseTranscription

Integration Transcription Translation

ReverseTranscriptase

Unintegrateddouble strandedViral DNA

Integratedviral DNA

ViralmRNA

Integrase

gag-polpolyprotein

1 2 3 4 56

Assembly andRelease

Protease InhibitorsIndinavir (Crixivan)Ritonavir (Norvir)

Saquinavir (Fortovase)Nelfinavir (Viracept)

Lopinavir/ritonavir (Kaletra)Atazanavir (Reyataz)

Fos Amprenavir (Lexiva)Tipranavir (Aptivus)Darunavir (Prezista)

NRTIsAZT (Zidovudine-Retrovir)

ddI (Didanosine-Videx)ddC (Zalcitabine-Hivid)d4T (Stavudine-Zerit)

3TC (Lamivudine-Epivir)ABC(Abacavir-Ziagen)

FTC (Emtricitabine, Emtriva)

NNRTIsEfavirenz (Sustiva)

Delavirdine (Rescriptor)Nevirapine (Viramune) (XR)

Etravirine (Intelense)Rilpivirine (Edurant)

Nucleus

Cellular DNA

HIV Virions

nRTITenofovir DF

(Viread)

Fusion InhibitorT-20

(Enfuvirtide, Fuzeon)

CCR5 AntagonistMaraviroc (Celsentri)

Integrase InhibitorRaltegravir (Isentress)

Elvitegravir /COBIDolutegravir (Trivicay)

Preferred Regimens

• EFV/TDF/FTC• ATV/r + TDF/FTC• DRV/r (once daily) + TDF/FTC• RAL + TDF/FTC•EVG/COBI/TDF/FTC•DTG + TDF/FTC•DTG + ABC/3TC[Pregnant Women Only: LPV/r (twice daily) + ZDV/3TC]

AlternativeRegimens

• EFV + ABC/3TC• RPV + (TDF or ABC)/(FTC or 3TC)• ATV/r or DRV/r + ABC/3TC• FPV/r or LPV/r (qd or bid) ABC/3TC or TDF/FTC• RAL + ABC/3TC

AcceptableRegimens

• EFV or RPV + ZDV/3TC• NVP + TDF/FTC or ZDV/3TC or ABC/3TC• ATV + (ABC or ZDV)/3TC• ATV/r, DRV/r, LPV/r, FPV/r , RAL + ZDV/3TC•MVC + ZDV or ABC/3TC•SQV/r + TDF/FTC or ABC/3TC or ZDV/3TC (with caution)

DHHS Guidelines May 2014: What to Start

DHHS Guidelines. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf . Revision March 27, 2012.

HIV Cascade

Physical Manifestations of Fat Redistribution Syndromes

Increased age-related complications on ART

Frieberg et al., JAMA Internal Med 2013

Increased risk of AMI in HIV compared to HIV uninfected

HR = 1.48 (CI = 1.27 – 1.72)

Further increase HR if CD4<200 or HIV RNA>500

Mea

n A

MI e

vent

s pe

r

100

0 pe

rson

yea

rs

N=82,459; Veterans Ageing Cohort Study Virtual Cohort

36

Liver Kidney

Bone

Brain

Cardiovascular System

Genitourinary Tract

Lifestyle

Etiology of non-AIDS-related events• Non-AIDS-related events are more common in HIV disease, even after

adjustment for age, cART exposure and traditional risk factors

Deeks SG, Phillips AN. Br Med J 2009;338:a3172

cART

toxicity

Persistentinflammation(immune activation)

Non-AIDS

events

(e.g. smoking)

Inflammatory biomarkers remain elevated during long-term ART

Neuhaus JID 2010

Early ART is associated with less inflammation during ART

ART-naïve with CD4+ count > 500 cells/mm3

Early ART Group

Initiate ART immediately

N=2,300

Deferred ART Group

Defer ART until the CD4+ count declines to < 350 cells/mm3

N=2,300

START

Tenofovir alenofenamide (TAF): reduced toxicity

Zolopa CROI 2013, Atlanta, GA # 99LB

0

10

20

30

40

50

60

70

80

90

100

2 4 8 12 16 24

% H

IV-1

RN

A <

50

c/m

L

Time (Weeks)

TAF/FTC/EVG/c 88% (n=112)

TDF/FTC/EVG/c 90% (n=58)

TAF/FTC/EVG/COBI

Rx-naïve, VL >5000, CD4 >50 (N=170)

Studies of Neuropathogenesis

Central Nervous System• Timing of treatment

• Reducing inflammation

• Select or enhanced CNS active ART

Prevention of non AIDS events

• Lifestyle modifications– Reduce smoking, healthy diet, exercise

• Reduce modifiable risk factors– Assessment of blood pressure, glucose and lipids

• Counselling and screening for common cancers

• Enhance CD4 recovery and reduce inflammation

Healthy aging requires aggressive

risk factor management (in

middle age), exercise and diet

Healthy aging requires aggressive

risk factor management (in

middle age), exercise and diet

Future Directions for Treatment• Enhancing linkage and retention into care

– Outreach, patient navigators, incentives

• Defining benefits of early therapy– Prevent end-organ dz, delay non-AIDS events, transmission

• Optimizing treatment– New treatments/new formulations– Minimize toxicity– Target end-organs (e.g. CNS)

• Direct interventions to address chronic inflammation– Antiinflammatory– Target underlying pathogenesis

Cure Research

Siliciano JD, et al. Nature Med 2003;9:727-8

Obstacle to cure: At least one….

• Control• Purge• Minimize• Combination interventions

Procedure and Events• Ablative chemotherapy

• Total body XRT• Graft vs. host

• Transplant with CCR5∆32 homozygous donor

Hutter G, et al. N Engl J Med 2009; 360:692-8.

Saez-Cirion A, et al. PLOS Pathogen 2013; 9:e1003211

ANRS VISCONTI-14

Persaud D, et al. 21st CROI 2014, Abstract #75LB; Persaud D, et al. N Engl J Med 2013; 369: 1828-35

• Undetectable for ~2 years, including by provirus DNA, SCA, VOA and non-induced genome assay

Original report

• Sept 2014 announced confirmed viral rebound

1. Henrich TJ, et al. JID 2013; 207:1694-702.2. Henrich T, et al. 7th IAS Conference. Kuala Lumpur, 2013. Abstract WeLBA05.

• Treatment Interruption2

– Patient A: 7 weeks without detectable HIV RNA in plasma or DNA in PBMC– Patient B: 15 weeks without HIV RNA in plasma, DNA in PBMC and negative

single copy assay

• Extensive testing in setting of full donor chimerism failed to identify evidence of HIV infection of donor cells1

– Negative outgrowth assays and PCR with large number of PBMC and CD4 cells– No HIV DNA from rectal tissue– No HIV specific cellular immune responses

Boston Stem Cell Transplants Revisited

Henrich TJ, et al. 21st CROI 2014, Abstract #144LB

Days Post ATI

Zinc Finger Nuclease: Targeting CCR5

Conclusion

• HIV continues to be a global pandemic• Early diagnosis has potential to impact individuals and

the public• Multiple new interventions have shown promise in

reducing HIV transmission• Advances in HIV treatment are unprecedented in

medicine– Major benefits of treatment are limited by low rates of HIV

testing as well as poor linkage and retention in care– Persistent inflammation may have long-term consequences to

those on suppressive therapy• Cure research is heating up, energized by a high profile

anecdote and a few false hopes

Thank You!!