New Therapeutic Agents and New Therapeutic Agents and Treatment GuidelinesTreatment Guidelines
Bruce Polsky, MDInterim Chairman, Department of Medicine
Chief, Division of Infectious DiseasesSt. Luke’s and Roosevelt Hospitals
New York, New York
Panel CD4 Count
US DHHS
June 1998 <500
February 2001 <350
April 2005 <200
International AIDS Society – USA Panel
July 1998 Any
January 2000 <500
July 2004 200
British HIV Association (BHIVA)
June 1998 >350
July 2003 201-350
July 2005 <200
Guidelines for Initiating Antiretroviral Therapy in Asymptomatic Patients:
1998–2005
The Rationale for Earlier Therapy
Easier, more effective, and less toxic therapy
Treatment Responses in First Year of HAART: Improving Over Time
4143 subjects from 5 clinic cohorts in Europe and Canada
Treatment-naïve; started HAART from 1996-2002
risk of virologic failure, med CD4 count increase in later years
– most “failure” now due to loss to follow-up or treatment discontinuation
Lampe F, et al. 12th Conference on Retroviruses and Opportunistic Infections (CROI). February 22-25, 2005. Boston, MA. Abstract # 593.
24.8 23.017.3
12.4 10 8 8.4
1996 1997 1998 1999 2000 2001 2002
% with > 500 copies/mL
0
20
40
60
80
100
% w
ith
VL
>50
0 o
n A
RT
0
30
60
90
120
150
Med
ian
CD
4 in
crea
se
97
119 120 121127 125
150Median CD4 increase
Incidence of Second Virologic Failure Declining Over Time
30
90
0
60
120 RR*=1.46
RR*=0.54
Inci
den
ce p
er 1
00 P
Y
RR*=0.51
RR*=0.82
REF
1998-1999
2004-2005
1996-1997
2000-2001
2002-2003
*Adjusted for time from HAART initiation, sex, age, AIDS, CD4 count, VL at HAART initiation and switch, and type of HAARTDeeks S, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 41.
113.6
15.117.9
41.5
70.7
Decline in New Cases of Resistance British Columbia: 1996-2007
Decline in new cases of resistance in province-wide data from BC Centre for Excellence in HIV/AIDS Drug Treatment Program
– 21,300 resistance tests from 5216 subjects
Year2008200620042002200019981996
New
cas
es o
f d
etec
ted
re
sist
ance
(n
)
0
600
500
400
300
200
100
3TCNRTINNRTIPIAny
Lima VD, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 895.
Pro
po
rtio
n S
urv
ivin
g
MonthsAIDS Surveillance Report, 2004. http://www.cdc.gov/hiv/topics/surveillance/resources/slides/epidemiology/index.htm.
Proportion Surviving FollowingAIDS Diagnosis: 1996–2003
0 12 24 36 48 60 72 84 96 108
1.00
0.75
0.50
0.25
0.00
20032002
20012000
19991998
19971996
The Rationale for Earlier Therapy
Easier, more potent, and less toxic therapy
Cohort studies showing benefit with earlier therapy
HAART and Survival Based on Initial CD4 Cell Count
Modeled data from ART Cohort Collaborative
10,855 patients included
934 progressed to AIDS or died
IDUs excluded from model
Sterne J, et al. 13th Conference on Retroviruses and Opportunistic Infections (CROI). February 5-8, 2006. Denver, CO. Abstract # 525.
<200 vs 201-350
<350 vs351-500
Hazard ratio for AIDS (95% CI)
3.68(3.01-4.51)
1.52 (1.10-2.10)
Hazard ratio for AIDS or death (95% CI)
2.93(2.41-3.57)
1.26(0.94-1.68)
Cumulative Probability of AIDS/Death According to CD4 Count at Initiation of HAART
Years since initiation of HAART0 1 2 3 4 5
0.00
0.02
0.04
0.06
0.08
0.10
0.12
Pro
ba
bil
ity
of
AID
S o
r d
ea
th
101-200 cells/mm3
201-350 cells/mm3
351-500 cells/mm3
The Rationale for Earlier Therapy
Easier, more potent, and less toxic therapy
Cohort studies showing benefit with earlier therapy
Better response to therapy
Pre-HAART CD4 Predicts Progression to AIDS: Johns Hopkins Cohort
Johns Hopkins HIV Cohort
Patients with virologic suppression for up to 6 yrs (N=280)
Only patients with baseline CD4 >350 returned to near normal CD4 count levels
Rate of progression to AIDS or death significantly higher over time in patients with CD4 <200 and 201-350 vs >350
*percent developing AIDS over 6 years of study†P<.05 compared with CD4+ <200.Moore RD, et al. 16th International AID Council (IAC). August 13-18, 2006. Toronto, Canada. Abstract # THPE0109.
0
100
200
300
400
500
600
700
800
900
0 1 2 3 4 5 6
CD
4 ce
lls/m
m³
13%*
12%*
1.5%*†
Year
> 350 cells/mm3
201-350 cells/mm3
< 200 cells/mm3
The Rationale for Earlier Therapy
Easier, more potent, and less toxic therapy
Cohort studies showing benefit with earlier therapy
Better response to therapy
Decreased transmission
Viral Load Affects Probabilityof HIV Transmission
GUD=genital ulcer diseaseGray R, et al. Lancet. 2001;357:1149-1153.
Log viral load (copies/mL)
GUDNo GUD
0
1.0
2.0
3.0
4.0
5.0
<1700 1700- 12500- 38500+
Pro
bab
ilit
y o
f tr
ansm
issi
on
/10
00 c
oit
al a
cts
The Rationale for Earlier Therapy
Easier, more potent, and less toxic therapy
Cohort studies showing benefit with earlier therapy
Better response to therapy
Decreased transmission
Prevent specific complications of HIV infection
HIV-Associated Complications That Are Less CD4-Dependent
Neurocognitive impairment
Non-Hodgkin’s lymphoma
Neuropathy
HPV-associated dysplasia/cancer
Kaposi’s sarcoma
The Rationale for Earlier Therapy
Easier, more potent, and less toxic therapy
Cohort studies showing benefit with earlier therapy
Better response to therapy
Decreased transmission
Prevent specific complications of HIV infection
Prevent non-opportunistic complications and death
D:A:D Study: CD4 Count Associated with Risk of Non-HIV Related Death
Cohort of >23,000 pts in Europe, Australia, USA
1248 (5.3%) deaths 2000–2004 (1.6/100 person-years)
– of these, 82% on ART
Weber R, et al. 12th Conference on Retroviruses and Opportunistic Infections (CROI). February 22-25, 2005. Boston, MA. Abstract # 595.
RR of death according to immune function and specific cause
1.0
10
100
0.1
RR
>500<50 50-99
100-199
200-349
350-499
CD4 cells/mm3
OverallHIVMalignancyLiverHeart
Risk of Death in Naïve Patients with CD4 Counts >350
24 cohorts and collaborations
Mortality in naïve patients w/ CD4 >350 higher than in matched general population controls
487 deaths; 4.9/1000 patient-years– HIV-related deaths: 79 (16.2%)– non-HIV–related deaths: 235 (48.3%)– unknown cause of death: 173 (35.5%)
Despite high CD4 counts, ↑ CD4 still associated with ↓ risk of death– rate ratio: 0.95 per 100 cells higher (95% CI: 0.90-0.99; P=.0185)
SMR=sex-standardized mortality ratioLodwick R, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 141.
HIV Risk Group Observed Deaths Expected Deaths SMR (95% CI)
MSM 117 97.08 1.21 (1.00-1.44)
Heterosexual 82 24.63 3.33 (2.65-4.13)
Injection drug user 227 22.22 10.21 (8.93-11.63)
When to Start Therapy:DHHS Guidelines 1/9/2008
AIDS or symptomatic HIV disease
Asymptomatic:
– CD4 <350
– Pregnancy
– HIV-associated nephropathy
– HBV coinfection when HB therapy required
When to Start Therapy:DHHS Guidelines 1/9/2008
CD4 >350
– Optimal time to start therapy unknown
– Considerations:
• Motivation and adherence
• Viral load
• Rate of CD4 decline
• Risk of sexual transmission(eg, discordant couples)
• Other comorbidities
Caveats!
Data guiding the initiation of therapy come from observational studies
Patients who start therapy with advanced disease may do poorly for reasons unrelated to their CD4 counts
We may never have data from controlled clinical trials
The Pros and Cons of a Randomized Trial
PROS
Could provide the definitive answer about when to start therapy
CONS
Previous attempts to enroll such trials have failed
Expensive
Observational data already compelling
Will the question or the chosen CD4 thresholds still be relevant by the time the results are available?
Caveats!
Data guiding the initiation of therapy come from observational studies
Patients who start therapy with advanced disease may do poorly for reasons unrelated to their CD4 counts
We may never have data from controlled clinical trials
Many patients present with advanced disease
When is ART Started?CD4 Count at Initiation, 2003-2005
42 countries, 176 sites; N=33,008
Since 2000, CD4 count at initiation in developed countries stable at ~150–200, increasing in Sub-Saharan Africa from 50 to 100
In US, CD4 at initiation lower than in many other resource-rich nationsEgger M, et al. 14th Conference on Retroviruses and Opportunistic Infections (CROI). Feb 25-28, 2007.Los Angeles, CA. Abstract # 62.
ACTG A5164: Improved Outcomes with Immediate ART During Acute
Opportunistic Infections Immediate vs deferred ART during acute OI
No difference in composite primary endpoint (virologic response, clinical progression, and death; P=.215)
Immediate treatment:
– less clinical progression/death through Week 48 (P=.035)
– shorter time to clinical progression or death (P=.023)
Safety and incidence of IRIS similar between groups
– ~62% of patients presented with PCP; potential impact of steroids?
Zolopa A, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 142.
When to Start During Acute Opportunistic Infections
Treat immediately
Conditions for which ART is best or only therapy:
– Progressive multifocal leukoencephalopathy
– Dementia– HIV-associated nephropathy
Kaposis Sarcoma
– Cryptosporidiosis
– Microsporidiosis
Conditions for which higher CD4 count improves prognosis
– Primary CNS lymphoma
– Non-Hodgkin's lymphoma
Consider delaying treatment
Potential for immune reconstitution inflammatory syndrome (IRIS)
– Tuberculosis
– M avium complex
– Cryptococcal meningitis
Potential for overlapping drug toxicity or interactions
– Tuberculosis
The New Drugs
DHHS Treatment Guidelines: 1/29/20082 NRTIs + Either NNRTI or PI
www.aidsinfo.nih.gov
NRTIs NNRTIs PIs
Preferred
ABC/3TC EFV ATV/r
TDF/FTC FPV/r BID
LPV/r BID
Alternative
AZT/3TC NVP ATV
Ddl + 3TC FPV
FPV/r QD
LPV/r QD
SQV/r
Targets for Antiretroviral Therapy
Reverse Reverse Transcriptase Transcriptase
InhibitorsInhibitors
Protease Protease InhibitorsInhibitors
Integrase Integrase InhibitorsInhibitors
EntryEntryInhibitorsInhibitors
PIs
NRTIs,NNRTIs
CCR5 Antagonists
Fusion Inhibitors
Antiretroviral Agents Approved in the US
NRTIs NNRTIs PIs
Zidovudine (AZT)—Retrovir
Nevirapine (NVP)—Viramune
Saquinavir (SQV)—Invirase
Didanosine (ddI)—Videx, Videx EC
Delavirdine (DLV)—Rescriptor
Indinavir (IDV)—Crixivan
Stavudine (d4T)—Zerit
Efavirenz (EFV)—Sustiva
Ritonavir (RTV)—Norvir
lamivudine (3TC)—Epivir
Abacavir (ABC)—Ziagen Nucleotide RTIs Nelfinavir (NFV)—Viracept
Emtricitabine (FTC)—Emtriva
Tenofovir DF (TDF)—Viread
Lopinavir/RTV (LPV/r)—Kaletra
Fusion Inhibitors Atazanavir (ATV)—Reyataz
Enfuvirtide (ENF, T20)— Fuzeon
Fosamprenavir (FPV)—Lexiva
Tipranavir (TPV)—Aptivus
Darunavir (DRV)—Prezista
Antiretroviral Agents Approved in the US
NRTIs NNRTIs PIs
Zidovudine (AZT)—Retrovir
Nevirapine (NVP)—Viramune
Saquinavir (SQV)—Invirase
Didanosine (ddI)—Videx, Videx EC
Delavirdine (DLV)—Rescriptor
Indinavir (IDV)—Crixivan
Stavudine (d4T)—Zerit
Efavirenz (EFV)—Sustiva
Ritonavir (RTV)—Norvir
lamivudine (3TC)—Epivir
Abacavir (ABC)—Ziagen Nucleotide RTIs Nelfinavir (NFV)—Viracept
Emtricitabine (FTC)—Emtriva
Tenofovir DF (TDF)—Viread
Lopinavir/RTV (LPV/r)—Kaletra
CCR5 Inhibitors Fusion Inhibitors Atazanavir (ATV)—Reyataz
Maraviroc (MVC)— Selzentry
Enfuvirtide (ENF, T20)— Fuzeon
Fosamprenavir (FPV)—Lexiva
Tipranavir (TPV)—Aptivus
Darunavir (DRV)—Prezista
HIV-1 Entry Inhibitors
Virus-CellFusion
gp41
gp120
V3 loop
CD4Binding
CD4
CellMembrane
CoreceptorBinding
CCR5/CXCR4(R5/X4)
CCR5 antagonistsMaravirocVicrivirocPRO140
Enfuvirtide
TNX-355
CXCR4 antagonists
CCR5CCR5
CD4CD4
CXCR4CXCR4
R5 Viruses Utilize the CCR5 co-receptor Also known as M-tropic or
nonsyncytium inducing (NSI) Transmitted variants Prevalent in early disease
X4 Viruses Utilize the CXCR4 coreceptor Also known as T-tropic or
syncytium inducing (SI) Emerge in later disease Associated with accelerated
CD4 decline and disease progression
Dual VirusesCan utilize either
co-receptor
Berger EA, et al. Nature. 1998;391:240.
T-Cell Surface
40
20
0
100
80
60
MOTIVATE 1 and 2: Combined Virologic Efficacy at Week 48P
atie
nts
(%
)
Time (wks)
16.7%
43.2%*
45.5%*
0 4 20 288 12 16 24 32 36 40 44 48
PBO + OBT (n=209)MVC QD + OBT (n=414)MVC BID + OBT (n=426)
*P<.0001 vs placeboHardy D et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 792.
Antiretroviral Agents Approved in the US
NRTIs NNRTIs PIs
Zidovudine (AZT)—Retrovir
Nevirapine (NVP)—Viramune
Saquinavir (SQV)—Invirase
Didanosine (ddI)—Videx, Videx EC
Delavirdine (DLV)—Rescriptor
Indinavir (IDV)—Crixivan
Stavudine (d4T)—Zerit
Efavirenz (EFV)—Sustiva
Ritonavir (RTV)—Norvir
lamivudine (3TC)—Epivir
Abacavir (ABC)—Ziagen Nucleotide RTIs Nelfinavir (NFV)—Viracept
Emtricitabine (FTC)—Emtriva
Tenofovir DF (TDF)—Viread
Lopinavir/RTV (LPV/r)—Kaletra
CCR5 Inhibitors Fusion Inhibitors Atazanavir (ATV)—Reyataz
Maraviroc (MVC)— Selzentry
Enfuvirtide (ENF, T20)— Fuzeon
Fosamprenavir (FPV)—Lexiva
Integrase Inhibitors Tipranavir (TPV)—Aptivus
Raltegravir (RAL)—Isentress
Darunavir (DRV)—Prezista
HIV Integrase Mechanism
X
Strand Transfer Inhibitors
BENCHMRK-1: Patients with Viral Load <50 copies/mL at Week 48
Pat
ien
ts (
%)
Weeks
RAL n =PBO n =
60
40
0
100
80
20
0 2 8 12 16 24 32 40 484
118 118 118 118 117 118 118232 231 231 230 229 232 229
118230
118231
33%
P<0.001
62%
31%
P<0.001
65%
Cooper DA , et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 788.
Raltegravir (RAL) vs Efavirenz (EFV) in ART-Naïve Patients
Pts randomized to TDF/3TC + EFV or RAL at 100, 200, 400 or 600 mg BID
– mean VL 4.6–4.8 log c/mL
– mean CD4 271–338
Adverse events similar
– more CNS AEs with EFV
– lower TC, LCL, TG with RAL
Markowitz M, et al. 4th International AIDS Society (IAS) Conference. July 22 – 25, 2007. Sydney, Australia. Abstract #TUAB104.
100
80
60
40
20
002 4 8 12 16 24 32 40 48
Week
RAL100 mg BID (n=39)RAL 200 mg BID (n=40)EFV 600 mg QD (n=38)
RAL 400 mg BID (n=41)RAL 600 mg BID (n=40)
Pts
wit
h V
L <
50 c
/mL
(%
)
VL <50 c/mL (95% CI) [NC=F]
DUET-1 and -2: VL <50 at Wk 48 Mean CD4 change at Week 48 significantly greater in
ETR arm: +98 vs +73 1,2
1. Haubrich R, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 790.
2. Johnson M et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 791.
Time (wks)
VL
< 5
0 c/
mL
at
Wk
48(%
± 9
5% C
I)
ETR (n=599)
PBO (n=604)
0 20 484032242 4 8 12 16
20
0
60
80
40
61%
40%
P<.0001
ITT-TLOVR
MOTIVATE 1 and 2: VL <50 at Wk 24 byNo. of Active Drugs in OBR
No. of active drugs in OBR
0
20
40
60
80
100
35
51
56
44
130
134
59
88
104
64
132 121
3
18
29
9
43 43
19
52 53 5561 58
0 1 2 ≥3
Pat
ien
ts (
%)
N =
Nelson M, et al. 14th Conference on Retroviruses and Opportunistic Infections (CROI). Feb 25-28, 2007.Los Angeles, CA. Abstract # 104aLB.Lalezari J, et al. 14th Conference on Retroviruses and Opportunistic Infections (CROI). Feb 25-28, 2007.Los Angeles, CA. Abstract # 104bLB.
PBO + OBRMVC QD + OBRMVC BID + OBR
0 20 40 60 80 100
BENCHMRK-1 and -2: Undetectable VL at Week 48, Overall, and by Genotypic
Sensitivity Score RALPBO
By GSS:
65
166
68
443
112
158
0
1
≥2
n
Patients (%)
228
92
6434
453
3767
5975
Overall
Cooper DA, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 788.
DUET-1 and -2: Viral Load <50 at Wk 48,by Active Agents in OBR
1. Haubrich R, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 790.
2. Johnson M, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 791.
3. Winters B, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 873.
VL
< 5
0 c/
mL
at
Wk
48 (
%)
20
0
40
60
80
100
33
60
26
76
61
12/36
121/203
51/196
229/300
187/305
0/35
0 1 2Number of active agents in OBR by PSS
(DRV active if FC <40)
ETR (n=599)Placebo (n=604)
The Goal of Therapy
The goal of therapy is virologic
suppression to <50 copies/mL in
all patients.
DHHS & IAS-USA Guidelines
The goal of therapy is virologic
suppression to <50 copies/mL in
all patients.
DHHS & IAS-USA Guidelines
1. US Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/guidelines. Accessed May 7, 2007.
2. Hammer S, et al. JAMA. 2006;296:827-843.