ART Advances-into the Next Decade

James Hakim MB MMed MSc FRCPProfessor of Medicine, University of Zimbabwe

AIDS 2010

Vienna-Austria18-23 July 2010

Antiretroviral Therapy Into the Next Decade

Historical perspectives

Current Status of ART

ART Into the Next Decade

Historical PerspectivesART Milestones

Vancouver Durban

Vancouver1996

Durban2000

Barcelona2002

Key ART Initiatives

UNGASS

WHO

UNAIDS

GFATM

PEPFAR

CHAI

UNITAID

National & Regional Initiatives

NGO & Other Initiatives

When/What is the next Milestone

• ? Universal Access

Status of ART Roll-Out 2009

• 5.2m PLH on ART– Most - MLIC

• Infection outstrips Treatment by 5:2

• 5m more need treatment

• 2010 WHO Guidelines takes this to 10 Mill

Achievements of ART

• Improved survival • Decreased

opportunistic infections

• Improved quality of life

Restores Hope & Dignity

Kim J, Farmer P. NEJM 2006

Mortality RLS vs RRS

• ART-LINC vs ART-CC comparisonsLow-INC High-

INC

Female 51% 25%

CD4 (base)

108 235

CD4 gain (6mths)

106 103

VL (6mths)<500c/ml

76% 77%

Mortality Adjusted HR1-6 mths - 4.3 (95%CI 1.6-11.8)7-12 mths-1.5 (95% CI 0.7-3.0)

Braitstein P. Lancet 2006;367;817

Mortality in RRS

• Resource rich settings– Increasing

importance of non-AIDS illnesses beyond second year

ART-CC CID 2010;50:1387

Mortality in RLS

• High early mortality after initiation of ART– Causes

• Tuberculosis• Acute sepsis• Cryptococcal disease• Malignancy (KS)• P jiroveci• Others

Lawn S. AIDS 2008;22:1897 Lawn S. AIDS 2009;23:335

Impact of time spent on various CD4 strata on mortality

Other Achievements of ART

• Impact:– Tuberculosis– Maternal and child mortality

» Hogan M, et al. Lancet 2010;375:1609

– Improves school attendance & workforce» Zivin J, et al. J Publ Econ 2009;93:1008» Thirumurthy H, et al. J Hum Res 2008;43:511

– HIV transmission» Donnell D, et al. Lancet 2010;375:2092

Impact on Tuberculosis

• Ecological analysis• Fall in TB

prevalence in HIV patients

• 1,250 pts in S. Africa

• RCT– Early vs Delayed

ART– 816 participants– TB cases:

• 18 vs 36 p=0.0125

2005 2008 P-value

All 3.2% 1.6% P=0.02

HIV+ve 9.2% 3.6% p=0.003

Rxd TB 4% 2.3% p=0.06

Middelkoop K, et al. IAS C Town 2009; Am J Resp Crit Care 2010; Jun 25

Severe P, et al. NEJM 2010;363:257

Early ART Delayed ART p-value

18 36 P=0.0125

ART in the Developing World

• Implementation has been greatly helped by WHO guidelines– 2002– 2003– 2006– 2010

2010 WHO ART Guidelines for Adults & Adolescents Guidelines

Early Initiation of ART CD4 threshold 350c/mm3

• CIPRA-HT-001– Severe P, et al. NEJM

2010;363:257

– 816 participants– Deaths:

• 6 vs 23 p=0.0011

• Cohort Analysis– Even higher

thresholds– 350-500– >500

– Kitahata MM, et al. NEJM 2009;360:1815

Guidelines-CD4 ThresholdsGuidelines CD4-Asymptomatic Pts

DHHS (2010) <350 (consider 500)

IAS (2010) <500

EACS (2008) <350 (consider >350)

BHIVA (2008 <350 (consider >350)

WHO EURO (2007/8) 200-350

WHO (2006) <200 (consider 200-350)

WHO (2010) <350

Treat Earlier-2010 WHO Guidelines

To start earlier is the right thing to do

“Harmonize treatment guidelines”

CD4<350 c/mm3

Seek and Treat (earlier diagnosis)

Public Health Approach

DART

CIPRAS. Africa

JinjaUganda

IAS July 2009 18

SurvivalSurvival

0.90

0.87

0.08

0.92

0.90

0.18

0.95

0.94

0.55

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

Pro

port

ion

aliv

e

Years from enrolment

Entebbe Cohort(Uganda):pre-ART 1996-2000, median CD4 75 at enrolment:57.7/100 PY

164 eventsLCM: 2.2/100 PYCDM: 2.9/100 PY

218 events

Survival at 5 yrs: LCM-90%, CDM-87%

Trained Lay Workers-monitoring ART

• Home-based vs Facility based care– End point-Virologic

Failure (RNA >500c/ml)

• 859 participants – (HBC-729 vs FBC-483)

• Rate Ratio:– 1.04 (95%CI 0.78-1.4)

HBC is as effective as FBC

Jaffar S, et al. Lancet 2009;374:2080

CIPRA South Africa

• Nurse monitored vs Doctor monitored– Randomized non-

inferiority trial

• Follow up-120 wks

Doctor monitored n=408

Nurse monitored n=404

Total Failure

179(44%) 192(48%)

Deaths 10 11

Virol Fail 44 39

Toxicity 68 66

LTFU 70 63

Nurse vs Doctor monitoring is non-inferiorHR 1.09 (95% CI 0.89-1.33)

Sanne I, et al. Lancet 2010;376:33

Antiretroviral Drugs

• NRTIs– Zidovudine– Lamuvudine– Stavudine– Didanosine– abacavir– Tenofovir– Emtricitabine

• NNRTIs– Nevirapine– Efavirenz– Etraverine

• Integrase Inhibitors– Raltegravir

• Protease inhibitors– Lopinavir– Atazanvir – Tipranavir– Darunavir– Indinavir– Ritonavir– Nelfinavir– Saquinavir– Amprenavir– Fosamprenavir

• Fusion Inhibitors– Enfuvertide

• CCR5 antagonists– Maraviroc

First-Line ART

• Harmonized to include TB and pregnant women

• ART to all TB and HBV patients• Preferred-NNRTI based regimen• Preferred use of TDF or AZT• d4T withdrawal and elimination

WHO 2010 Guidelines

Second-Line ART

• Boosted PI-based regimens– Poor evidence of efficacy of NRTI

backbone in public health approach– High resistance mutations when failure is

clinically or immunologically diagnosed» Hosseinipour M, et al. AIDS 2009;23:1127

– ? Immediate use of new classes/drugs immediately (RAL, ETV, Darunavir)

Second-Line ART

• Need for studies to provide evidence for public health approach to second line regimens– EDCTP trial-EARNEST (enrolling)– ACTG trial– Other

• The place of PI/r monotherapy

Third-Line ART

• Real need to treat those failing second-line ART

• Can this be addressed with public health approach principles?

– ? Need for resistance testing– WHO 2010 recommends drugs eg DRV,

ETV, RLV– Does this obviate resistance testing?

Monitoring

• Issues – Efficacy tests (CD4, RNA VL)

• Cost• Lab capacity• Impact on pace of roll-out• Need for evidence-based monitoring

– Evidence for RNA VL monitoring is good-but availability to date is limited

• Need for roll-out of low-cost point-of-care tests– CD4, RNA VL, resistance testing

Monitoring

• Toxicity tests– CBC

• Chronic illness, AZT, malignancies, malnutrition, etc

– Renal function test (which? creatinine, urine)• TDF

• Other– Tropism tests, HLAB5701 (ABC)

Into the Next Decade• Pipeline for new

antiretroviral drugs• The pace of

development has slowed in this area

Into the Next Decade

• Current drugs are efficacious with good safety and tolerance– But there is still need for drugs that are:

• More efficacious• Better tolerated (Better adherence)• More safe (Less monitoring)• More forgiving (Less resistance)• Compatible with TB, pregnancy, hepatitis,

malaria, etc...

Treatment 2.0

Into the Next Decade

Address long- term non-AIDScomplications

Cardiovascular

Neuro-congnitive

Hepatic

Renal

SMART. NEJM 2006;355:2283DAD NEJM 2007;356:1723

Bone

Into the Next Decade

• Non-AIDS outcomes– unmitigated HIV replication or ART

• cardiovascular, hepatic, renal, bone, neuro-cognitive effects, cancer

• Aging/senescence

Limited data from RLSMore research required

Into the Next DecadeLaboratory Monitoring

• Accelerate roll-out of Point-of-care technology– CD4 counts– RNA Viral Load– Resistance– Other

HIV Eradication

• A preventive HIV vaccine is an important intermediate step

• The eradication and cure of HIV remains the only victory that we can celebrate

• The science and strategy required to achieve this is of the highest priority

• Granich R. Lancet 2009;373:48• Hütter G. NEJM 2009;360:692• Carter C. Nature Med 2010;16:446

Conclusions-Current

• The last decade has seen a momentous expansion of ART in LMIC

• We continue to see the benefits of ART in improved survival, reduction in disease progression & improved quality of life

• ART impacts non-AIDS conditions in both negative and positive ways. This must continue to be a focus of research

ConclusionsInto the Next Decade

• The quest for more efficacious, better tolerated, safer and more forgiving antiretroviral drugs must continue

• Better delivery modes of ART are needed to improve access to all

• Preventive value of ART has come of age-pMTCT and beyond...

• HIV cure remains the ultimate prize in the response to AIDS

Acknowledgements

• UCSF– Diana Havlir

• ARASA– Michaela Clayton

• Univ of Zimbabwe– Anthony Chisada– Nehemiah Nhando– Wadzanai Samaneka

– Mike Chirenje

• YRG-Care– Kumar Kumarasamy

• University of Denver– Thomas Campbell

• WHO– Marco Vitoria

• Slides & Comments– Many

Thank You