Current Clinical Controversies in the Treatment of HIV/AIDS Paul E. Sax, MD Paul E. Sax, MD Clinical Director, Division of Infectious Diseases and HIV Program Brigham and Women’s Hospital Associate Professor of Medicine Harvard Medical School Boston, Massachusetts
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Current Clinical Controversies in the Treatment of HIV/AIDS Paul E. Sax, MD Clinical Director, Division of Infectious Diseases and HIV Program Brigham.
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Current Clinical Controversies in the Treatment of HIV/AIDS
Paul E. Sax, MDPaul E. Sax, MD
Clinical Director, Division of Infectious Diseases and HIV Program
Brigham and Women’s HospitalAssociate Professor of Medicine
Harvard Medical SchoolBoston, Massachusetts
2
Faculty:Content Development and Training
Calvin J. Cohen, MD, MSResearch Director, CRI New England
Clinical Instructor, Harvard Medical SchoolBoston, Massachusetts
Medical Director, Orlando Immunology CenterOrlando, Florida
Paul E. Sax, MDClinical Director, Division of Infectious Diseases and HIV Program
Brigham and Women's HospitalAssociate Professor of Medicine, Harvard Medical School
Boston, Massachusetts
Learning Objectives (CME, CE, CPE) At the completion of this educational activity, participants
should be able to:— Describe and discuss current controversies regarding
HIV treatment— Identify key studies that potentially can improve
outcomes with HIV treatment — Summarize the clinical data supporting methods for
improving the health and management of HIV-infected patients
4
Current Clinical Controversies in the Treatment of HIV/AIDS
1. When to Start: 2009 DHHS Guidelines
2. What to Start: 2009 DHHS Guidelines
3. Benefits and Limits of Simplification
4. Adoption of Opt-out Testing
5. Potential Strategies for HIV Prevention
6. The Importance of Non-AIDS Co-Morbidities
5
2009 DHHS Guidelines: Recommendations for Initiation of ART in Naïve Patients
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision December 1, 2009.
Strength of Recommendation: A = Strong; B = Moderate; C = Optional Quality of Evidence for Recommendation: I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion
Note: HIV RNA >100,000 c/mL and decline of CD4+ count > 100 cells/mm3 per year favor starting ART
Clinical CategoryCD4 Cell Count
(cells/mm3)2009 DHHSGuidelines Strength-Quality
AIDS-defining illness Any value TreatA-I
Asymptomatic
<350 Treat
350 to 500 Treat A/B-II: 55% A vs. 45% B
>500 Treat/Optional B/C-III: 50% B vs. 50% C
Pregnancy, HIV-associated nephropathy, HIV/HBV when HBV treatment indicated
Any value Treat A-III
6
SMART: Influence of CD4+ Count and Treatment on Clinical Event Rate
Last CD4+ Cell Count (cells/mL)
<250 250–349
350–499 ≥500 Overall
Immediate ART
Person-yrs (%)*
10 (2.6)
30 (7.9)
109 (28.8)
230 (60.7)
379(100)
Rate** 10.4 6.7 1.8 0.0 1.3
Deferred ART
Person-yrs (%)*
19 (6.4)
65 (21.7)
118 (39.5)
97 (32.4) 299 (100)
Rate** 16.0 9.2 7.6 3.1 7.0
Emery S et al. 4th IAS, Sydney, 2007. Abstract WEPEB018.Emery S et al. 4th IAS, Sydney, 2007. Abstract WEPEB018.
Opportunistic Disease and Death
Cum
. Pro
babi
lity
(X10
0) 25
Months
Deferred ARTImmediate ART
HR = 4.38 (95%CI, 1.45–13.2); P=.009
5
20
10
15
00 84 12 16 20 24 28 32 36
Serious Non-AIDS (CV, Renal, CA)
HR = 7.05 (95% CI, 1.58–31.5); P=.01
36
Cum
. Pro
babi
lity
(X10
0)
Deferred ARTImmediate ART
5
20
10
25
15
00 84 12 16 20 24 28 32
Months *Time spent in the CD4+ cell count category censored at event**per 100 person years
7
NA-ACCORD: Risk of Death with ART Deferral
351-500 CD4+ >500 CD4+
RR 95% CI P RR 95% CI P
Deferral of ART 1.7 1.3, 2.3 <0.001 1.9 1.4, 2.8 <0.001
● HIV RNA was not an independent predictor of mortality● Exclusion of IDU or HCV did not affect overall relative risk● Rate of virologic suppression (<500 c/ml) higher in pts who started ART earlier
Kitahata M, et al. New Engl J Med 2009;360:1815-26.
8
ART-CC: When Should ART be Started?
Hazard ratios for AIDS or death, adjusted for lead time/unseen events
Sterne J, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 72LB.
Magnitude of increase in CD4 cell count greatest if therapy started at low CD4 cell counts, but greater likelihood of CD4 cell count
normalization with earlier therapy
1. Moore R, et al. Clin Infect Dis. 2007;44(3):441-446; 2. Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.
Likelihood of Achieving a Normal CD4 Cell Count Depends on Where You Start
1000
800
600
400
200
0
0 48 96 144 192 240 288 336
ATHENA National Cohort2
Weeks From Starting ART
<5050-200200-350350-500≥500
Years on ART
Johns Hopkins HIV Clinical Cohort1
Mea
n C
D4
Cel
l C
ou
nt
(cel
ls/m
m3)
0 1 2 3 4 5
200
400
600
800
0
1000
<200
201-350
>350
10
● Patients initiating ART should be willing and able to commit to lifelong treatment and understand the benefits and risks of ART and the importance of adherence
● Patients and clinicians may defer therapy based on clinical or personal circumstances
● The decision to defer should depend on CD4 count and viral load
● Deferring therapy may be considered for:- Adherence barriers- Comorbidities that complicate or prohibit ART- Elite controllers/Long-term nonprogressors
2009 DHHS Guidelines: Conditions Where Deferral of Therapy Might be Considered
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision December 1, 2009.
11
Current Clinical Controversies in the Treatment of HIV/AIDS
1. When to Start: 2009 DHHS Guidelines
2. What to Start: 2009 DHHS Guidelines
3. Benefits and Limits of Simplification
4. Adoption of Opt-out Testing
5. Potential Strategies for HIV Prevention
6. The Importance of Non-AIDS Co-Morbidities
12
DHHS Guidelines: TDF/FTC a part of all Preferred Regimens for Treatment-Naïve Patients
• EFV + (ABC or ZDV)/3TC• NVP + ZDV/3TC• ATV/r + (ABC or ZDV)/3TC• FPV/r (once or twice daily) + either [(ABC or ZDV)/3TC1] or TDF/FTC• LPV/r (once or twice daily) + either [(ABC or ZDV)/3TC1] or TDF/FTC• SQV/r + TDF/FTC
AcceptableRegimens
• EFV + ddI + (3TC or FTC)• ATV + (ABC or ZDV)/3TC
InsufficientData
• MVC + ZDV/3TC• RAL + (ABC or ZDV)/3TC• (DRV/r or SQV/r) + (ABC or ZDV)/3TC
Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
13
Studies Comparing ABC/3TC and TDF/FTC
A5202 HEAT ASSERT
Sponsor NIAID GSK GSK
Sample Size 1858 (797 HIV RNA > 100,000 c/mL)
688 385
Blinding Double-Blind Double-Blind None
3rd Drug EFV or ATV/r LPV/r QD EFV
Primary Endpoint Time to Virologic Failure*
<50 c/mL at 48 wks Change in GFR at wk 48 by MDRD
HLA-B*5701 Testing Permitted, not required No Required, only negative pts enrolled
Key Results For those with HIV RNA >100,000 c/mL, study stopped early due to higher rate of virologic failure with ABC/3TC
ABC/3TC non-inferior
No difference in eGFR; proportion <50 c/mL favored TDF/FTC (71% vs. 59%; difference 11.6%, 95% CI 2.2-21.1); Total hip and lumbar spine BMD decline more with TDF/FTC
Recent Exposure*: yes/noCumulative Exposure: per year
**
Rel
ativ
e R
isk
of
MI (
95%
CI)
Adjusting for eGFR does not change ABC MI finding:Adjusted RR 1.89; 95% CI (1.46 – 2.44; p=0.0001)
21
VA Case Registry: Use of ABC or VA Case Registry: Use of ABC or TDF in Last Regimen and Risk of MITDF in Last Regimen and Risk of MI
Bedimo R, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOAB202.
Unadjusted HR of AMI for each PY of exposure to each one of the categoriesAdjusted for estimated GFR prior to regimen onset (by MDRD method)
NRTI in last regimenduring obs. period
ABC TFV Both ABC and TFV
Haz
ard
rat
io
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
22
DHHS Guidelines:Criteria for Preferred PI
● The following criteria distinguish between preferred and alternative PIs:1. Superior or noninferior virologic efficacy compared to another
PI regimen, with at least 48-week data published;2. No more than 100mg of ritonavir per day;3. Once-daily dosing;4. Low pill count; and5. Good tolerability
● Using these criteria, ATV/r QD and DRV/r QD are preferred PIs
Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
23
DRV/r and ATV/r in ARV-Naïve Patients: Higher Response Rates than LPV/r
Adapted from: 1. Mills A, et al. AIDS May 29, 2009 [Epub ahead of print]; 2. Molina J-M, et al. 48th ICAAC/46th IDSA , Washington, DC, 2008. Abst. H-1250d
*Estimated difference in response vs LPV/r for superiority: ITT = 8.3% (95% CI 1.8;14.7, P=0.012)
ARTEMIS1
(ITT, TLOVR)*96 weeks
LPV/r QD or BID
DRV/r 800/100 QD
79
71
n=343n=346
0
20
40
60
80
100
CASTLE2
(ITT, NC=F)96 weeks
ATV/r300/100 QD
LPV/r400/100 BID
6874
0
20
40
60
80
100
n=443 n=440Pat
ien
t P
erce
nt
<50
co
pie
s/m
L
24
ARTEMIS: DRV/r Better Tolerated than LPV/r
Grade 2–4 adverse events*≥2% incidence, n (%)
DRV/r (N=343)
LPV/r (N=346)
Mean exposure (weeks) 95.0 91.4
Any grade 2–4 AE at least possibly related 80 (23) 119 (34)
GI AEs (all AEs) 23 (7) 52 (15)
Diarrhea 14 (4)‡ 38 (11)
Nausea 6 (2) 10 (3)
Rash (all types) 9 (3) 5 (1)
*Excludes laboratory abnormalities reported as adverse events; ‡p<0.001 vs LPV/r; no other AEs showed a statistically significant difference between the two treatment arms
Mills A, et al. AIDS May 29, 2009 [Epub ahead of print].
25
CASTLE:ATV/r Better Tolerated than LPV/r
a Through 96 weeksb Excluding lab abnormalities reported as AEs
1. Soriano V, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-924c;2. Heera J, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009. Abst. TUAB103.
ARTEN: Comparison of NVP and ATV/r in ARV-naïve pts starting at CD4+ <400 (Men)
and <250 (Women) (N=569)1
MERIT-ES: Comparison of EFV and MVC in ARV-Naïve Patients with an R5 screening
result by enhanced Trofile assay2
6259
0
20
40
60
80
100
MVCEFV
Week 48 <50 c/mL Week 96 <50 c/mL
• D/C for AEs: 15.5% EFV vs. 6.1% MVC
• Virologic failures: 5.9% EFV vs. 12.5% MVC
Pat
ien
ts (
%)
wit
h H
IV R
NA
<50
c/m
L
35
Current Clinical Controversies in the Treatment of HIV/AIDS
1. When to Start: 2009 DHHS Guidelines
2. What to Start: 2009 DHHS Guidelines
3. Benefits and Limits of Simplification
4. Adoption of Opt-out Testing
5. Potential Strategies for HIV Prevention
6. The Importance of Non-AIDS Co-Morbidities
36
Potential Treatment Simplification Strategies
● Substitution of co-formulation for individual agents (e.g., EFV + TDF/FTC to EFV/TDF/FTC)
● Substitution for a single component of the regimen (e.g., ENF to RAL) to improve tolerability or decrease/prevent toxicity
● Dose or regimen de-escalation (e.g., Discontinuation of RTV or PI/r monotherapy)
● Maximizing the use of PK properties to achieve less drug exposure (e.g., FOTO)
37
Simplification Improves Adherence
* Using the Mixed Effect ModelDeJesus E, et al. ICAAC, San Francisco, 2009. # H1572
Analysis of Three Once-daily HAART Regimens by Daily Pill Burden*Analysis of Three Once-daily HAART Regimens by Daily Pill Burden*
● Enrolled pts with HIV RNA <50 c/mL on LPV/r BID regimen in combination with at least 2 NRTIs- No limit on number of prior
ART regimens- Prior virologic failure not an
exclusion- No lipid lowering therapy
for at least 12 weeks
● Randomized (1:1) to continue LPV/r or switch to RAL
Eron J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 70aLB.
SWITCHMRK 1 SWITCHMRK 2
RAL
(N=174)
LPV/r
(N=174)
RAL
(N=176)
LPV/r
(N=178)
HIV RNA
≤ 50 c/mL94.3% 92.5% 96.0% 95.5%
Mean CD4 (cells/mm3) 478 508 471 482
LPV/r ≤ 1 yr 16.7% 17.8% 17.6% 18.5%
Median yrs prior ART(min, max)
3.3
(0.3, 22.3)
3.6 (0.5,
20.2)
3.7 (0.5,19.2)
4.6 (0.6,16.3
)
Median # prior ART(min, max)
5.0
(4.0, 16.0)
5.0 (2.0, 5.0)
5.5 (3.0,13.0)
6.0 (4.0,14.0
)
40
● Statistically significant improvements in total cholesterol, non-HDL cholesterol and triglycerides were observed following switch to RAL
● Further Analysis underway to assess factors associated with failure after switch to RAL- Previous Resistance: 84% with confirmed HIV RNA >50 c/mL) in the RAL group were not on 1st
ART regimen; 66% with history of VF on prior regimen(s)- NRTI Backbone: Virologic failure rate higher on ABC/3TC than TDF/FTC
SWITCHMRK 1 and 2:Virologic Outcomes (NC = F)
Eron J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 70aLB.
Per
cen
t H
IV R
NA
<50
Co
pie
s/m
L
50
60
70
80
90
100SWITCHMRK 1
0 4 8 12 24Weeks
81%
87%
(95% CI) : -6.6 (-14.4, 1.2)
0 4 8 12 24Weeks
94%
88%
(95% CI) : -5.8 (-12.2, 0.2)
SWITCHMRK 2
41
SWITCHMRK 1 and 2:Lower Response with ABC than TDF
ABC** 20/25 80.0 (59.3, 93.2) 22/23 95.7 (78.1, 99.9) -15.7 (-35.9, 4.1)**The difference in response was similar in study 033 (-12.9 % for ABC vs -4.6% for TDF)**plus FTC or 3TC
42
MONET: Simplification to DRV/r QD Monotherapy
Arribas J, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. TUAB106.
N=2562NRTIs + PI/r or NNRTI
HIV RNA<50 X 6 monthsNo h/o VF; DRV naive
N=2562NRTIs + PI/r or NNRTI
HIV RNA<50 X 6 monthsNo h/o VF; DRV naive
DRV/r 800/100 mg QD + 2 NRTI* (n = 129)
DRV/r 800/100 mg QD (n = 127)
96 wks96 wks
DRV/r + 2NRTIs DRV/r
HIV RNA < 50copies / mL, ITT, TLOVER,S=F 85.3% 84.3%
HIV RNA < 50 at last visit 97.7% 97.6%
Primary PI mutation 1 1
Grade 2-4 GI AEs ≥ 2% incidence 3.9% 5.5%
Grade 2-4 GI AEs ≥ 2% incidence( all types ) 1.6% 1.6%
ALT > 5 x ULN 1.6% 4.8%
Total Cholesterol > 300mg / dL, sustained 1.6% 4.8%
43
IMANI III: Lopinavir/r QD Monotherapy
● 48 week open-label pilot study
● Evaluated efficacy, safety and tolerability of LPV/r QD monotherapy in pts with undetectable VL while in active follow-up post IMANI I or after completion of IMANI II (LPV/r BID in ARV-naïve patients)
LPV/r QD monotherapy for simplification: Caution warranted until results from larger ongoing
studies evaluated
Gathe J, et al. 12th EACS; Cologne, Germany; November 11-14, 2009. Abst. PS 4/5.
IMANI III
31 Subjects
IMANI I
4 Subjects
IMANI II
27 Subjects
2 protocol defined
failures at Week 36
1 LFTU at
Week 48
27 Subjects
Week 48
SubjectBaseline
Mutations Week VLOn Treatment
Mutations
007 L63P 36 4,145M461, I54V, I62V, L63P,
V82A
021L63P, A71T
36 3,582L10V, V32I,
M46I/W, I47V, L63P, A71T
44
DHHS Guidelines:Regimen Simplification
● Switching patients with an extensive treatment history from LPV/r to RAL should be done with caution
● RAL can safely substitute for ENF in patients not previously treated with integrase inhibitors
● Any drug substitution may introduce unanticipated adverse effects or drug-drug interactions
● PI/r monotherapy studies have reported mixed results and should not be regarded as a clinical strategy until further data are available
Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
45
Current Clinical Controversies in the Treatment of HIV/AIDS
1. When to Start: 2009 DHHS Guidelines
2. What to Start: 2009 DHHS Guidelines
3. Benefits and Limits of Simplification
4. Adoption of Opt-out Testing
5. Potential Strategies for HIV Prevention
6. The Importance of Non-AIDS Co-Morbidities
46
Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf; http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5514a1.htm
2009 DHHS Guidelines: Opt-out Testing
● Patients must be identified early in the course of HIV infection, making earlier initiation of therapy an option
● Most HIV-infected patients are not diagnosed until they are at much later stages of disease
● For the current treatment guidelines to have maximum impact, opt-out testing per current CDC recommendations is essential
47
CDC Recommendation for HIV Testing in Adults and Adolescents
● Routine, voluntary, HIV screening for all persons aged 13–64 years, not based on risk
● Opt-out HIV screening• Opportunity to ask questions and option to decline
● Consent for HIV test is part of general consent for care• Separate consent not recommended• Prevention counseling not required in conjunction with HIV screening
● Low-prevalence setting• If yield from screening <0.1%, continued routine screening not warranted
Branson BM et al. MMWR Recomm Rep. 2006;55(RR-14):1-17.
48
Removing Written Consent Increases HIV Testing Rates
● After HIV testing opt-out policy change, rate of HIV tests per 1000 patient-visits increased 4.38 (CI, 2.17–6.60, p<0.001)
● No increase in ordering of other tests (hematocrit or creatinine) or of HIV testing in control setting without policy change
● Increase occurred across all patient populations and led to a rise in newly-diagnosed HIV
Zetola PLoS One. 2008;3(7):e2591
20
15
10
5
0
HIV
Te
sts
per
1,0
00
pat
ien
t -v
ts
0 6 12 18 24 30 36
MonthsJuly 2004 June 2007
Before Policy After Policy
SFGH HIV Tests
50
40
30
10
0Te
sts
per
1,0
00 v
isit
s
0 6 12 18 24 30 36
MonthsJuly 2004 June 2007
Before Policy After Policy
Creatinine Tests
20
20
15
10
5
0
HIV
Te
sts
per
1
0,0
00
Lab
ora
tory
t
0 6 12 18 24 30 36
MonthsJuly 2004 June 2007
Before Policy After Policy
Control University-based Medical Center HIV Tests
Hematocrit Tests
50
40
30
10
0Te
sts
per
1,0
00 v
isit
s
0 6 12 18 24 30 36
MonthsJuly 2004 June 2007
Before Policy After Policy
20
49
Changing HIV Testing Laws: Impact on Survival
● Comparison of diagnosis rates in states with opt-out vs. opt-in testing
● In states with opt-out testing, HIV is diagnosed at a higher CD4 cell count better treatment outcomes
● Computer-based simulation model of HIV disease applied to these data
● If all remaining states switched to opt-out, potential national survival gain would be > 600,000 life years
April M, et al. 47th IDSA Meeting, Philadelphia, 2009. Abst. 1254
50
HIV Testing Expansion: Earlier Diagnosis, Higher CD4 Counts
● Program to expand testing in medical and jail settings in Washington, DC began in 2006
● Since program began, patients diagnosed with higher CD4 counts at initial testing
● During first 18 months of program, increase in median CD4+ count at diagnosis to 332 cells/mm3
Median CD4+ Countat Time of Testing
215
187 198220
262
332
183
0
50
100
150
200
250
300
350
2001 2002 2003 2004 2005 2006 2007
Year of HIV Diagnosis
Me
dia
n C
D4
Co
un
t
Hader S, et al. 16th CROI; 2009; Montreal. Abstract 57.
Why is Opt-out Screening Not Being Implemented in All States?
● Need to reduce stigma and discrimination before universal testing
● Before universal testing there must be universal prevention counseling for HIV-negative and treatment and care for HIV-positive
● Broad testing leading to increase in numbers of HIV- positive patients entering into care could potentially have grave consequences due to a lack of funding and healthcare resources
● While it is everyone’s human right to know their HIV status, they also have the right to decide when and where they will be HIV tested
The Global Network of People living with HIV, Scaling up HIV Testing: Different perspectives; http://www.gnpplus.net/component/option,com_docman/task,cat_view/gid,245/Itemid,53/?mosmsg=You+are+trying+to+access+from+a+non-authorized+domain.+%28search.yahoo.com%29; Accessed 12/10/09
53
Current Clinical Controversies in the Treatment of HIV/AIDS
1. When to Start: 2009 DHHS Guidelines
2. What to Start: 2009 DHHS Guidelines
3. Benefits and Limits of Simplification
4. Adoption of Opt-out Testing
5. Potential Strategies for HIV Prevention
6. The Importance of Non-AIDS Co-Morbidities
54
First Positive HIV Vaccine Trial
● 16,401 patients enrolled from 2003-2005 in Thailand in placebo-controlled trial
● Intervention: Canarypox ALVAC-HIV and glycoprotein 120 AIDSVAX B/E (“boost)
Ongoing ARV based Prevention (Oral PrEP and Topical Microbicide) Trials (September 2009)
BMGF-BI & Melinda Gates Foundation; CAPRISA – Centre for the AIDS Programme of Research in South Africa; CDC – US Centers for Disease Control and Prevention; FHI – Family Health International; FTC – emtricitabine; IAVI – International AIDS Vaccine Initiative; MTN – Microbicide Trials Network; NIH – US National Institute of Health; Q1-4 – quarters 1-4; TDF – tenofovir disoproxil fumarate; USAID – United States Agency for International Development
56
A Major PrEP Issue:Is it Cost-Effective in the US?
● Computer simulation of HIV acquisition, detection, and care to model PrEP among MSM at high risk of HIV in US
● Model assumed 50% PrEP efficacy and TDF/FTC $753/month● Base-case: $298,000/Quality-adjusted life year (QALY) – not
generally considered cost-effective by US standards
Paltiel AD, et al. Clin Infect Dis 2009;48:806-815..
2009 DHHS Guidelines: Preventing Secondary Transmission of HIV
● Essential tools for prevention of sexual and blood-borne transmission of HIV include:- Consistent and effective use of ARV therapy, resulting in a
sustained reduction in viral load;- Consistent condom usage;- Safer sexual and drug use practices; and- Detection and treatment of STIs
● Medical visits provide an opportunity to:- Reinforce HIV prevention messages;- Discuss sexual- and drug-related risk behaviors;- Diagnose and treat intercurrent STIs; and
- Develop open communication between provider and patient
Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
58
HIIV Treatment Reduces the Risk of Transmission
ARV StatusCY
ObservationNo. LinkedInfections
InfectionRate (C-Y)
Infection RateRatio (95% CI)
Not on ARV 5,062 171 3.4/100 ---
On ARV 547 4 0.7/100 0.21 (0.08, 0.59)
On ARV –conservative*
547 6 1.0/100 0.32 (0.14, 0.73)
● Sexual risk behaviors lower in those on ART (19% vs 25%, P<0.05)● Both ART and change in behavior independently reduced HIV
transmission
*Includes 2 partners who seroconverted in the same 3-month interval when the HIV-infected partner initiated ARVs
2,993 couples were followed for a median of 512 days
HIV-free Survival of HIV-negative partners,by ARV status of HIV+ Partner
0
2073920
500
1035475
1000
598256
1500
25269
2000
806
2500
00
0.0
0.2
0.4
0.6
0.8
1.0
Su
rviv
al P
rob
ab
ilit
y
Days
Off ARV On ARV
CensoredLogrank P<.0001
Sullivan P, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 52bLB.
59
Potential Impact of “Test and Treat” Strategy on HIV Epidemic and Use of ART
Granich R, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOPL101.
Strategy: Universal ARTART if CD4+ <350 cells/mm3No ART
0.0000.0050.0100.0150.020
Inc
ide
nc
e/y
ea
r
0.00
0.05
0.10
0.15
Pre
va
len
ce
0.00
0.05
0.10
0.15
1980 2000 2020 20400.000
0.005
0.010
Mo
rta
lity
/ye
ar
0.000
0.005
0.010
1980 2000 2020 2040
HIV ART
Pro
po
rtio
n o
f ad
ole
scen
ts a
nd
ad
ult
s 15
yea
rs o
r o
lder
0.0000.0010.0020.0030.0040.005
60
Concerns Regarding Using “Test and Treat” Strategy
1. Crepaz N et al. JAMA 2004;292:224-236; 2. Vernazza PL, et al. AIDS 2000;14:117-21; 3. Marcelin, A-G, et al. AIDS 2008;22:1673-81.
HIV RNA detected in semen of 7/145 (5%) of men with VL <40 c/mL
#
HIV RNA in seminal
plasma (c/mL) ARV combination
1 940 ZDV, 3TC, IDV, RTV
2 257 3TC, EFV, LPV/r
3 1230 ZDV, 3TC, LPV/r
4 255 TDF, FTC, AZT
5 802 ZDV, 3TC, IDV, RTV
6 267 FTC, ATV, RTV
7 620 TDF, FTC, EFV
HIV in semen in ARV naïve and ARV treated men with VL <400
0%
20%
40%
60%
80%
100%
HIV-RNA HIV-DNA
Pe
rce
nta
ge
of
pa
tie
ns
wit
h
de
tec
tab
le H
IV i
n s
em
en Controls (drug naïve ) n=55
Effective treatment n=114
P<0.0001P<0.0001
P<0.01P<0.01
● Patients who believe that ART or an undetectable viral load protects against transmitting HIV have higher rates of unprotected sex (OR 1.82; 95% CI, 1.52-2.17)1
● While HIV RNA significantly lower in semen of pts on ART with an undetectable plasma HIV RNA, still detectable in some2,3
61
Current Clinical Controversies in the Treatment of HIV/AIDS
1. When to Start: 2009 DHHS Guidelines
2. What to Start: 2009 DHHS Guidelines
3. Benefits and Limits of Simplification
4. Adoption of Opt-out Testing
5. Potential Strategies for HIV Prevention
6. The Importance of Non-AIDS Co-Morbidities
62
Life Expectancy of ARV-treated Patients by CD4 Nadir
Depending on when HAART is started, life expectancyduring modern HAART era is 10 to 30 years less than that
in uninfected patients
CD4+ Nadir (cells/mm3) < 100 100-200 >200
Life expectancy at age 20 (years)
32 42 50
ART-Cohort Collaboration. Lancet. 2008;372:293-299 (see also Lohse N, et al. Ann Intern Med. 2007;146:87-95 and Lewden C, et al. J Acquir Immune Defic Syndr. 2007;46:72-77.)
Life Expectancy by CD4+ Nadir When HAART Started
63
Kaplan RC, et al. Clin Infect Dis. 2007; 5:074-1081.
Traditional Health Related Risk Factors More Prevalent Among HIV-positive Patients
0 10 20 30 40 50 60 70 80
0 10 20 30 40 50 60 70 80
Prevalence, % (95% CI)
High LDL Level
Low HDL Level
HighTriglycerides Level
Hypertension
Smoking
Overweightor Obese
Diabetes
HIV+ Men
HIV- Men
HIV- Women
HIV+ Women
64
Many Non-AIDS Events Appear to be Higher in Treated HIV Disease than Controls
Phillips A, et al. 15th CROI; 2008; Boston. Abstract 8.
Is Lower Current CD4 Cell Count Significantly Associated With Increased Risk of non-AIDS Events?
67
DHHS Guidelines: T-cell Activation and Inflammation
● Early untreated HIV infection associated with sustained high-level inflammation and T-cell activation which are associated with disease progression
● ART results in a rapid, but often incomplete, decrease in most markers of HIV-associated immune activation- Persistent inflammation, as represented by levels of IL-6, may be
associated with risk of death
● These observations support earlier use of ART:- Treatment decreases the level of inflammation and T-cell
activation; and- Degree of residual inflammation and/or T-cell dysfunction during
ART is higher in patients with lower CD4 cell nadirs and earlier treatment may result in less residual immunological perturbations
Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
68
Current Clinical Controversies in the Treatment of HIV/AIDS