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Transcript of Current Challenges in the Management of HIV Sharon Walmsley Professor of Medicine University of...
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