Current Challenges in the Management of HIV

Sharon Walmsley

Professor of Medicine

University of Toronto

Senior Scientist, Toronto Hospital Research Institute

Objectives

Review the advances achieved in the management of HIV especially the impact on morbidity and mortality

Discusses the challenges that continue despite the advances with HAART therapy

Describe the increasing epidemic of comorbidity

Describe the impact of the changing management of HIV and the importance of considerations of drug interactions

Triumphs

Improved morbidity and mortality Improved antiretroviral formulations to optimize adherence Improved short term tolerability and decreased some long

term adverse events of therapy Prevention of maternal to child transmission Decreased drug resistance Ability to better manage the treatment experienced patient

The impact of HAART on SurvivalThe impact of HAART on Survival

Adapted from Lohse N, et al. Ann Intern Med 2007;146:87–95

Pro

bab

ilit

y of

su

rviv

al

Pre-HAART (1995–1996)

Early HAART (1997–1999)

Survival from age 25 yearsN = 3,990

1

0.75

0.5

0.25

0

25 30 35 40 45 50 55 60 65 70

Age (years)

Late HAART (2000–2005)

Population controls

Combivir1,2, Trizivir1,2,3, Kivexa2,3, Truvada4,5, Atripla4,5,6

ARVs: 2011

NRTI/NtRTI NNRTI Protease Fusion

ZDV Nevirapine Saquinavir Enfuvirtide

3TC Efavirenz Indinavir

ddI Etravirine Nelfinavir Integrase

Abacavir Ritonavir Raltegravir

Tenofovir Fosamprenavir

FTC Lopinavir/r CCR5

D4T Atazanavir/r Maraviroc

Tipranavir/r

Darunavir/r

RegimenRegimen DHHSDHHS IASIAS EACSEACS

EFV/TDF/FTCEFV/TDF/FTC PreferredPreferred RecommendedRecommended RecommendedRecommended

DRV/r + TDF/FTCDRV/r + TDF/FTC PreferredPreferred RecommendedRecommended RecommendedRecommended

ATV/r + TDF/FTCATV/r + TDF/FTC PreferredPreferred RecommendedRecommended RecommendedRecommended

RAL + TDF/FTCRAL + TDF/FTC PreferredPreferred RecommendedRecommended AlternativeAlternative

EFV + ABC/3TCEFV + ABC/3TC AlternativeAlternative AlternativeAlternative RecommendedRecommended

LPV/r + TDF/FTCLPV/r + TDF/FTC AlternativeAlternative AlternativeAlternative RecommendedRecommended

NVP + TDF /FTCNVP + TDF /FTC AlternativeAlternative RecommendedRecommended

US Department of Health and Human Services Guidelines; Revised December 1, 2009. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf; Thompson MA, et al. JAMA 2010;304(3):321-333; www.eacs.eu.

Improved ARV formulations

Fixed-dose combinations - the standard of care

One pill once a day for HIV is a realityOne pill once a day for HIV is a reality

Toxicity Was a Major Reason for Discontinuation of First-Line ARV

ICONA study group (March 1997 - June 1999)

– Median follow-up:45 weeks

– Study population: 862 ARV-naive patients

– 84.3% receiving unboosted PI + NRTIs

– Discontinuations: n = 312 (36%)

58%

14%

8%

20%

Cause of Discontinuation

d’Arminio Monforte A, et al. AIDS. 2000;14:499-507.

ToxicityFailure

NonadherenceOther

Safety and Tolerability of Select Current Regimens Are ImprovedSafety and Tolerability of Select Current Regimens Are Improved

StudyStudy Length Length Drug RegimensDrug Regimens Discontinuations Due to AEs, %Discontinuations Due to AEs, %

GS934GS934[1][1] 96 weeks96 weeks EFV + TDF + FTCEFV + TDF + FTCEFV + ZDV/3TCEFV + ZDV/3TC

551111

KLEANKLEAN[2][2] 48 weeks48 weeks FPV/RTV + ABC/3TC FPV/RTV + ABC/3TC LPV/RTV + ABC/3TCLPV/RTV + ABC/3TC

12121010

ARTEMISARTEMIS[3][3] 96 weeks96 weeks DRV/RTV + TDF/FTCDRV/RTV + TDF/FTCLPV/RTV + TDF/FTCLPV/RTV + TDF/FTC

4499

CASTLECASTLE[4][4] 96 weeks96 weeks ATV/RTV + TDF/FTCATV/RTV + TDF/FTCLPV/RTV + TDF/FTCLPV/RTV + TDF/FTC

3355

HEATHEAT[5][5] 96 weeks96 weeks LPV/RTV + ABC/3TC LPV/RTV + ABC/3TC LPV/RTV + TDF/FTCLPV/RTV + TDF/FTC

6666

M05-730M05-730[6][6] 48 weeks48 weeks LPV/RTV QD + TDF/FTC LPV/RTV QD + TDF/FTC LPV/RTV BID + TDF/FTCLPV/RTV BID + TDF/FTC

5533

GEMINIGEMINI[7][7] 48 weeks48 weeks SQV/RTV + TDF/FTCSQV/RTV + TDF/FTCLPV/RTV + TDF/FTCLPV/RTV + TDF/FTC

4477

STARTMRK STARTMRK [8][8]

48 weeks48 weeks EFV + TDF/FTCEFV + TDF/FTCRAL + TDF/FTCRAL + TDF/FTC

6633

MERIT MERIT [9][9] 96 weeks96 weeks EFV + AZT/3TCEFV + AZT/3TCMRV + AZT/3TCMRV + AZT/3TC

151566

1. Pozniak AL, et al. JAIDS. 2006. 2. Eron J Jr, et al. Lancet. 2006. 3. Ortiz,et al AIDS 2008. 4. Molina JM, et al. Lancet, 2008. 5. Smith K, et al.AIDS, 2009. 6. Gathe J, et al. JAIDS, 2009, 7. Walmsley SL, et al. JAIDS, 2009. 8. Lennox et al, Lancet 2009, 9. Cooper et al, JID, 2010

Therapy works for most for the long term7 year follow-up

Study 720: LPV/RTV Study 903E: EFV

Murphy HIV Clin Trials 2008;9:1-10 Cassetti IAS 2008, abstract #TUPE0057

81%95%

59%

Not only in clinical trials but also in practice

Raboud, Walmsley, 2010

Can I Have Children?Contraception and Pregnancy Issues in HIV

TriumphsTrends in reduction of MTCT: results over time in the field

McIntyre J, et al 12th CROI 2005; #8

USA and Europe Thailand Africa

% T

ran

smis

sio

n

0

5

10

15

20

25

30

35

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

PRIMARY RESISTANCEPRIMARY RESISTANCEHas continued at low levelsHas continued at low levels

1 1 XIII IHDRW, Tenerife, June 2004; XIII IHDRW, Tenerife, June 2004; 2 2 Wensing AMJ, XII IHDRW, June 2003, #117; Wensing AMJ, XII IHDRW, June 2003, #117; 3 3 Delfraissy JF,Delfraissy JF, Rapport 2004Rapport 2004

USA: ~10%1

Canada~8.5%1

Europe:~112*

UK: ~181†

Mexico: ~7%1

Australia:~131

France: ~123‡

Spain: ~9.51

Argentina 7-15%

Brazil 0-30%

Kaplan-Meier curves for the proportion of patients without virologic failure by the presence of minority

HIV-1 drug-resistant variants

0.0

0.2

0.4

0.6

0.8

1.0

Pro

port

ion w

ithou

t vir

olo

gic

failu

re

0.0 250 500 750 1000 1250 1500

Days

Minority variants not detectedMinority variants detected

p <0.001

The proportion of patients in North America who experience failure of at least two distinct regimens has declined dramatically (n ~ 30,000)

aRR=1.46

aRR=0.82

aRR=0.51 aRR=0.54

REF

Adjusted RR from cohort-stratified Cox model adjusting for time from HAART initiation, sex, age, AIDS, CD4 and VL at HAART initiation and switch, type of ARV (PI, NNRTI, NRTIs only) at initiation

Deeks CID 2009;49:1582

Tribulations

We still debate when to start therapy Response rates not increased above 80% at 48 week Short and long term adverse events Difficult to treat patients- depression, IVDU Emerging co-morbidities HIV as an inflammatory condition Inability to eradicate the reservoir Costs and access

When to Start ART ?

EARLY

Later

Much better ARV drugs - Potency - Simplicity Tolerability Larger number of options Deleterious effect of HIV Reduction HIV transmission Long term ART

Complications CostUncertainty ?

Fewer arguments not to start ART early

What is the impact of starting late?

Impaired immunological response to HAART1

Increased HIV-related and non-HIV related mortality2

Increased HIV-related sequelae3

Increased HAART-related complications4

Increased onward transmission5

Increased health care costs6

1. Robbins GK et al. Clin Infect Dis 2009; 48:350–361 2. Marin B, et al AIDS 2009;23:1743–53 3. Sabin CA et al. AIDS 2004;18:2145–51 4. Florence et al. HIV Medicine 2003;4:255–262 5. Marks G, et al. AIDS 2006;20:1447–50 6. Fimpel et al. Eur J Health Econ 2009; epub.

Kelly CF et al. CID 2009;48:787-794.

CD4 Nadir Impacts Ability of Effective HAART Treatment to Increase CD4 >500 cells/mm3

NA-ACCORD study: Higher mortality when deferring treatment

0.00

0.05

0.10

0.15

0.20

0 2 4 6 8 10

Years after 1996

CD4 count >500 cells/mm3

& defer HAART(N=6,539)

CD4 count >500 cells/mm3

& initiate HAART (N= 2,616)

Kaplan-M

eier survival estim

ates

Kitahata M, et al CROI 2009. Abstract 71

When to start antiretroviral therapy ?

CD4+ Cell Count

EACS DHHS IAS

< 350 cells/mm³

Start Start Start

350-500 cells/mm³

Start if Start Start

-Treatment recommended if- hepatitis C co-infection, -HBV,-HIVAN-VL>105 c/ml and/or CD4 decline >50-100/mm3/year or age >50 or, pregnancy, -high cardiovascular risk, malignancy.

Pathogenesis of HIV

HIV

Immune activationInflammation Immune deficit

Cardiovascular riskBone

Cognitive disorders Cancers

Immune deficitAccelerated aging

Cancers

AIDSCancers

HBV/HCV

HIV is deleterious - immune suppression and activation

SMART and DART HIV replication is associated to increased

mortality and morbidity

Treatment interruption vs continuing therapy

Event STI CT RR PN/100py N/100 py

AIDS/death 3.3 1.3 2.6 <10-4

AIDS (WHO stage 4) 8.3 3.2 2.6 0.003

NEJM 2006;355: 2283-96

SMART : Risk of Death and increases in markers of inflammation and coagulation

Marker Un-adjusted Adjusted

OR (4th/1st) P-Value OR (4th/1st) P-Value

Hs-CRP 2.0 0.05 2.8 0.03

Amyloid A 2.2 0.07 2.6 0.09

Amyloid P 0.7 0.39 1.1 0.84

IL-6 8.3 <0.0001 11.8 <0.0001

D-Dimer 12.4 <0.0001 26.5 <0.0001

F1.2 1.0 0.92 1.2 0.66

*Adjusted for age, race, ART, VL, BMI, Cholesterol, Smoking, Hepatitis, Statins, BP med’s

Kuller LH, et al. PLoS Med. 2008;5:e203.doi;10.1371/journal.pmed.0050203

AGE

10-15 years10-15 years

Non HIV related Comorbidities appear to occur earlier

INC

IDE

NC

E

HIV+HIV+ HIV-HIV-

The START studyWhen to start ART therapy?

Patients HIV+ with CD4 >500 cp/ml

Early TherapyStart cART immediately

n=600 in the initial phasen=1500 (estimation) in the final

phase

Deferred therapyStart cART when CD4

<350 cells/µL or symptoms n=600 in the initial phasen=1500 in the final phase

Gordin et al. IAS 2007, MOSY205 oral presentation

Tribulations:Recent Randomized ARV Trials

Gemini 64-65% Startmrk 82-86%KLEAN 65-66% ACTG 5202 83-89%ACTG 5142 (Wk 96) 77-89% Arten 70-75%Artemis 78-84% Altair 82-95%Merit 65-69% Aires 81-86%MK 004 87%

Naïve Trials Naive Trials

Proportion with VL <50 copies/mL Week 48 (ITT)

Triumph: Randomized ARV Trials in Treatment Experienced Patients

Benchmrk (Wk 24) 63% 89%Victor E1 (Wk 24) 64% 72%Motivate 42-47% 52-61% Power 46% 73%Duet 59% 66-80% TITAN 61-70% 60-80%

% VL< 50/ml at week 48

All Patients Patients with >2 active agents

Difficult to Treat Populations Impact of DepressionWIHS and MACS Cohorts

Cohort N Outcomes Predictors

WIHS[1] 961 Virologic response Immunologic response Clinical response

Continuous use of ART Absence of depression

WIHS[2] 1371 Increased probability of ART utilization for women identified as depressed

Antidepressants + mental health therapy Mental health therapy alone NOT antidepressants alone

MACS[3] 873 Interruption of ART Age, race, geography, HIV-1 RNA, depression, time on ART, lower adherence, no 3TC

Discontinuation of ART Age, HIV-1 RNA, depression, ABC, LPV

1. Anastos K, et al. J Acquir Immune Defic Syndr. 2005;39:537-544.2. Cook JA, et al. AIDS Care. 2006;18:93-100.3. Li X, et al. J Acquir Immune Defic Syndr. 2005;38:320-328.

P < .05

Difficult to Treat Populations IVDU Prospective study (interview) of Hopkins cohort (N = 764) of patients with nadir CD4+ count < 500

cells/mm³ or peak HIV-1 RNA > 30,000 copies/mL Adherence, virologic, and immunologic outcomes poorer among current IDUs

Lucas G, et al. J Acquir Immune Defic Syndr. 2001;27:251-259.

P < .001

Former usersNonusers

Active users

Change in HIV-1 RNA

-1.7-1.6

-0.8†

Pat

ient

s R

epor

ting

Non

adhe

renc

e (%

)

Nonadherence CD4+ Count Increase

24

17

34

116 122

65*

0

10

20

30

40

50

P = .11

Cha

nge

in C

D4+

Cou

nt

(cel

ls/m

m³)

25

50

75

100

125

Cha

nge

HIV

RN

A-1

(lo

g1

0 c

opi

es/m

L)

-2.0

-1.5

-1.0

-0.5

*P = .003 vs nonusers and former users; †P < .001 vs nonusers and former users. 0

0

-2.5

The drugs are better butOngoing issues with toxicity

Anemia

Lipoatrophy/ lipohypertrophy

Renal problems

Osteoporosis

Cardiovascular diseases

Impact of HIV, inflammation, aging, ARV

Are we seeing more Neurocognitive Disorders (HAND)?

HIV-Associated Dementia (HAD)

Mild Neurocognitive Disorder (MND)

Asymptomatic Neurocognitive Impairment (ANI)

Asymptomatic Neurocognitive Impairment (ANI)

No Neurocognitive Impairment No Neurocognitive Impairment

Reduced bone mineral densityIncreased prevalence of osteoporosis or osteopenia in spine, hip or forearm:63% of HIV+ patients2

Renal dysfunction

30% of HIV+ patients have abnormal kidney function1

Gupta SK et al. Clin Infect Dis 2005;40:1559–1585. ,Brown TT et al. J Clin Endocrinol Metab 2004;89(3):1200–1206, Clifford DB. Top HIV Med 2008;16(2):94–98Triant VA et al. J Clin Endocrinol Metab 2007;92:2506–2512, Patel P et al. Ann Intern Med 2008;148:728–736

Cardiovasculardisease

Neurocognitive dysfunctionNeurological impairment present in ≥50% HIV+ patients3

CancerIncreased risk of non-AIDS-defining cancerse.g. anal, vaginal, liver, lung, melanoma, leukemia, colorectal and renal5

75% increase in risk of acute MI4

Tribulations: We have failed to Eliminate the Viral Reservoir

Intensification with Raltegravir

Buzon et al, Nature Medicine, 2010

Nature MedicineVolume:

16,Pages:

460–465Year published:

(2010

Nature MedicineVolume:

16,Pages:

460–465Year published:

(2010

Nature MedicineVolume:

16,Pages:

460–465Year published:

(2010

We will not solve the problem with antivirals alone

Multi-Class Failure: Tomorrow

+ failure on ENF and RAL

Heavily NRTI experienced with multiple mutations

ARV therapy in the developing world

Access is Improving but not good enough

Treatment for Prevention

Can it work

Will it work

Can we afford it?

Viral Load as a predictor of Heterosexual HIV transmission

Quinn et al, N Engl J Med. 2000;342:921-929

HAART stops HIV replication

HIV load falls to undetectable levels in plasma

as well as in sexual fluids

Sharp reduction in HIV transmission

Impact of ART Sero-discordant Heterosexual Couples

S Attia, M Egger, M Muller, M Zwahlen and N Lowa. AIDS. 2009 Jul 17;23(11):1397-404

92% reduction in HIV Transmission Risk from 5.64 to 0.46 transmissions per 100 person-years

Conclusions

HAART has dramatically improved the lives of persons with HIV

Despite our advances problems remain as we continue to cope with challenges of adverse events both short and long term, the increase in comorbidity, aging, and issues around adherence

The difficult to treat population needs new management strategies

We need to go beyond the virus, and think of the deleterious impact of inflammation

We have made some inroads into prevention