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During this presentation, Dr. Calvin Cohen tackles the subject of co-formulations and their impact on patient adherence to treatment. He further discusses the factors to consider when choosing the best treatment for an individual patient and addresses the topic of the long-term effects that these treatments have on the life expectancy of patients. PROGRAM HIGHLIGHTS ⎯ Antiretroviral combined treatments ⎯ Impact of co-formulations on patient adherence ⎯ The best treatment for each patient ⎯ Life expectancy of HIV patients ⎯ Long-term effects of HIV medications on patients' lives
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ARV therapy: From Our Roots Comes Our Growth
Calvin Cohen, MD, MSc Research Director, CRI New England
Harvard Vanguard Medical Associates Harvard Medical School
Boston, USA This activity is supported by an educational grant from:
Lessons Learned
Three an(virals leads to durable suppression
If three are good, are four be7er?
ZDV/3TC/EFV vs ZDV/3TC/ABC/EFV
Adapted from Gulick R, et al. 45th ICAAC; December 16-‐19, 2005; Washington, D.C., Abstract H-‐416a.
Adapted from Markowitz M et al. 18th CROI; Boston MA; Feb 27-‐Mar 2 2011. Abst 148LB
Our 2013 An=retroviral Library: Currently Approved (in the US)
NRTIs • Abacavir
• Didanosine • Emtricitabine • Lamivudine • Stavudine • Tenofovir
• Zidovudine
PIs • Atazanavir • Darunavir
• Fos-‐Amprenavir • Indinavir • Lopinavir • Nelfinavir • Ritonavir
• Saquinavir • Tipranavir
NNRTIs • Delavirdine • Efavirenz • Etravirine
• Nevirapine (XR) • Rilpivirine Entry inhibitors
• Maraviroc
Integrase inhibitors • Raltegravir
• Elvitegravir* • Dolutegravir
Fusion Inhibitors • Enfuvirtide
PK booster • Cobicistat*
*Only available coformulated with TDF/FTC
Suppression: How Many Drugs are Op=mal?
• One – Boosted PI Monotherapy
• Two – Boosted PI and one more ARV – And Other approaches…
• Three – The current Standard of Care – Two NRTIs + a 3rd ARV
• More?
Cahn P et al. 14th EACS; Brussels, Belgium; October 16-‐19, 2013. Abst. LBPS7/6.
Dual Therapy (DT): LPV/r 400/100 mg BID + 3TC 150 mg BID
(n=217)
Triple Therapy (TT): LPV/r 400/100 mg BID + 3TC or FTC
and a third inves=gator-‐selected NRTI in fixed-‐dose combina=on (n=209)
ARV-‐ naive pa=ents ≥18 years
HIV RNA >1,000 copies/mL No IAS-‐USA defined NRTI or PI
resistance at screening HB(s)Ag nega=ve
(N=426)
Stra=fied by Screening HIV RNA
(≤ or > 100,000 copies/mL)
Week 24 Interim Analysis
Week 48 Primary Endpoint
Cahn P et al. 14th EACS; Brussels, Belgium; October 16-19, 2013. Abst. LBPS7/6.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
BSL W4 W8 W12 W24 W36 W48
DT TT
Per
cent
Pat
ient
s
P=0.171, difference +4.6% [Cl 95%: -‐2.2% to +11.8%]
88.3 83.7
Week
VL <50 copies/mL (ITTe)
Preferred Regimens: Regimens with op=mal and durable efficacy, favorable tolerability and toxicity profile, and ease of use
NNRTI: EFV/TDF/FTC
EFV – cau(on for women given risk of birth defects when EFV used in first trimester
PI: ATV/r + TDF/FTC DRV/r (once daily) + TDF/FTC
ATV/r should not be used in pa(ent who require >20 mg omeprazole equivalent per day
Int: RAL + TDF/FTC RAL dosing BID
2013 DHHS Guidelines: What to Start: Four Preferred
Available at: h7p://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013
Preferred Regimens: Regimens with op=mal and durable efficacy, favorable tolerability and toxicity profile, and ease of use
NNRTI: EFV/TDF/FTC
EFV – cau(on for women given risk of birth defects when EFV used in first trimester
PI: ATV/r + TDF/FTC DRV/r (once daily) + TDF/FTC
ATV/r should not be used in pa(ent who require >20 mg omeprazole equivalent per day
Int: RAL + TDF/FTC EVG/cob/TDF/FTC DTG + TDF/FTC or ABC/3TC
RAL dosing BID
Nov 2013 DHHS Guidelines: What to Start: Seven Preferred
Available at: h7p://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013
www.clinicaltrials.gov
The START Study
• Sample Size Increased in 2013 to 4,600 – addi(onal n=600 >35 years old – Enrolled >4,400 as of Oct 2013
• Hypothesis: early ART reduces rate of primary endpoint by 28.8% – 43% for AIDS events; 24% for non-‐AIDS events
Early ART group Ini=ate ART immediately following randomiza=on
N=2,300
Deferred ART group Defer ART un=l the CD4 count declines to <350 cells/mm3 or
AIDS develops N=2,300
ART Naïve HIV-‐infected individuals Confirmed CD4 count >500 cells/mm3
Even Just to Prevent HIV Transmission
• Though we know how HIV is transmi7ed…
3,5
1,7
0 0
1
2
3
4
5
6
Unprotected RAI**
Protected RAI**
Exclusively fella=o
Percen
t
Preven=ng HIV Transmission Safer Sex: the HOT Study
" Cohort study of MSM • N = 439 • Six month observa(on period • Oral sex: No HIV infec(ons observed despite lack of condom use (94%)
" Conclusions: • Rate of transmission via oral sex is lowest
• Not zero: <0.8%
* HIV incidence determined in repeat testers ** RAI = recep=ve anal intercourse
Adapted from Page-‐Shafer K, et al. XIV Intl AIDS Conference, Barcelona 2002, #4872; Balls et al. We PpC2072, Bangkok 2004
D:A:D: Predic=ng Cardiovascular Disease Risk in HIV
*Full D:A:D CVD predic=on model included age, gender, systolic BP, smoking status, family history of CVD, diabetes, total cholesterol, HDL, CD4 count, cumula=ve exposure to PIs and NRTIs, and current use of ABC. Reduced model omits ARV.
Friis-Moller N, et al. 14th EACS; Brussels, Belgium; October 16-19, 2013. Abst. PS1/3.
Risk factor Per unit D:A:D Full*
Age ln 22.0
Sex 1.37
Diabetes 1.96
Smoking current / former
2.25 / 1.24
Total and HDL cholesterol ln 2.58 / 0.61
Systolic BP (#: if treated)
ln 4.59
Family History CVD 1.37
SPIRIT NCEP: Categorical Analysis of LDL
22%
17%
45%
29%
42%
48%
37%
33%
22%
22%
15%
24%
11%
10%
3%
11%
4%
3%
1%
2%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Week 24
Baseline
Week 24
Baseline
<100 mg/dLOptimal 100 to 129 mg/dL Optimal/ Above Optimal 130 to 159 mg/dL Borderline High 160 to 189 mg/dL High ≥190 Very High
RPV
/FTC
/TD
F Im
med
iate
Sw
itch
PI/r+
2NR
TIs
At Week 24, P<0.001 for comparison between groups (Cochran-Mantel-Haenszel Row Mean Score test using modified ridit scores)
Tebas P, et al. IDSA 2013. San Francisco, October 2-‐2, Abstract 672
<5.5 mmol/L 5.5 to 7.16 mmol/L 7.2 to 8.8 mmol/L 8.9 to 10.5 mmol/L >10.6mmol/L
SPIRIT Categorical Analysis of Total Cholesterol:HDL Ra=o
RPV
/FTC
/TD
F Im
med
iate
Sw
itch
PI/r
+ 2N
RTI
s
At Week 24, P<0.001 for comparison between groups (Cochran-Mantel-Haenszel Row Mean Score test using modified ridit scores)
Tebas P, et al. IDSA 2013. San Francisco, October 2-‐2, Abstract 672
D:A:D: Predic=ng Cardiovascular Disease Risk in HIV
*Full D:A:D CVD predic=on model included age, gender, systolic BP, smoking status, family history of CVD, diabetes, total cholesterol, HDL, CD4 count, cumula=ve exposure to PIs and NRTIs, and current use of ABC. Reduced model omits ARV.
Friis-‐Moller N, et al. 14th EACS; Brussels, Belgium; October 16-‐19, 2013. Abst. PS1/3.
Risk factor Per unit D:A:D Full*
Age ln 22.0
Sex 1.37
Diabetes 1.96
Smoking current / former
2.25 / 1.24
Total and HDL cholesterol ln 2.58 / 0.61
Systolic BP (#: if treated)
ln 4.59
Family History CVD 1.37
CD4 cell count 2-‐fold higher 0.89
Abacavir -‐ current 1.47
PI -‐ cum. exposure year 1.05
NRTI – cum.exposure year 1.03
ACTG 5224s: Biomarkers of Inflamma=on High Sensi=vity CRP
McComsey G, et al. 19th CROI; Sea7le, WA; March 5-‐8, 2012. Abst. 835.
STaR Virologic Suppression at Weeks 48 & 96 by Baseline HIV-‐1 RNA Stra(fied by 100,000 c/mL – Snapshot Analysis
7.6
0 -‐12% 12%
Favours EFV/FTC/TDF
Favours RPV/FTC/TDF
7.2 1.1 13.4
0.2 15.1
W48
W96
0
10
20
30
40
50
60
70
80
90
100
<100k
Baseline HIV-‐1 RNA, c/mL
231/ 260
204/ 250
205/ 260
178/ 250
HIV-‐1 RNA, <50 c/m
L (%
)
89
82 79
71
Cohen C, et al. EACS Brussels 2013, LBPE7/17
W48 W48 W96 W96
STaR: Adverse Events Leading to Discon=nua=on of Study Drug through Week 96
RPV/FTC/TDF (n=394)
EFV/FTC/TDF (n=392)
Discon=nua=ons* Due to Adverse Event (AE), n (%) 12 (3.0%) 43 (11.0%)
AE leading to discon=nua=on in >1 subject in either arm
Nervous System Disorders
Dizziness 0 6 (1.5%)
Psychiatric Disorders
Abnormal Dreams 0 5 (1.3%)
Insomnia 1 (0.3%) 4 (1.0%)
Depression 0 8 (2.0%)
Suicidal Idea=on 0 3 (0.8%)
Nightmare 0 2 (0.5%)
GI, General, Skin Disorders
Diarrhea 0 2 (0.5%)
Fa=gue 0 2 (0.5%)
Pyrexia 0 2 (0.5%)
Toxic Skin Erup=on 0 2 (0.5%)
33 Cohen C, et al. EACS Brussels 2013, LBPE7/17
Time to Suicidality, primary analysis
Hazard ratio (95% CI) 2.28 (1.27 to 4.10), p=0.006
47 events/5817 PY* (8.08/ 1000 PY)
15 events/4099 PY* (3.66/1000 PY)
Mollan K, et al. IDWeek 2013. San Francisco, CA. #670.
Awempted/Completed Suicide, 2ndary
analysis
Death Compe=ng Risk
Mollan K, et al. IDWeek 2013. San Francisco, CA. #670.
Overall Grade 2-‐4 CNS adverse events were significantly decreased by Week 4 and also at Week 12 (P<0.001)
UK Mul=center Study ATR to EPA Switch due to CNS toxicity (Week12)
Nelson M, et al. ICAAC 2013. Denver, CO. #H-‐672b
Propor=on of individual Grade 2-‐4 CNS Adverse Events
80
70
60
50
40
30
20
10
0
Prop
ortio
ns (%
)
Week 4 Baseline
Week 12
P=0.008
P=0.029
P=0.001
P=0.021
P=0.005
P=0.008
P=0.564
P=0.003
P=0.034
P<0.001
Each CNS adverse event, except headache, showed sta(s(cally significant improvement (P<0.05)
-12% +12%
-1.1 4.1 9.2
4.2 10.3 -1.9
-1.6 3.6 8.8
5.1 9.4 0.7
2.5 7.4 12.3
Differences in Percentages (95% CI)
1.1 7.2 13.4
9.5 17.3 1.7
-20 -15 -10 -5 0 5 10 15 20
Efficacy: Newer Treatments Outperform EFV Favours EFV Favours Comparator
GS-1021 (STB vs. ATR) N=700 88% vs. 84% (Snapshot)
GS-102/103/1042 (STB vs. ATR) N=1124 89% vs. 84% (Snapshot)
STaR3 (CPA vs. ATR) N=786 86% vs. 82% (Snapshot) 89% vs. 82% (Snapshot) BLVL ≤100,000 cpm
STARTMRK4 (RAL vs. EFV) N=566 86% vs. 82% (ITT, NC=F) 71% vs. 61% (ITT, NC=F)
SINGLE5 (DTG vs. ATR) N=833 88% vs. 81% (Snapshot)
Week 48: Non-inferiority shown
Week 48 (Pooled): Statistically significant higher VL response
Week 48: Non-inferiority shown
Week 48: Statistically significant higher VL response
Week 48: Non-inferiority shown
Week 48: Statistically significant superior VL response
Week 240: Statistically significant higher VL response
1. Sax P, et al. Lancet 2012;379:2429–38 2. Ward D, et al. ICAAC 2012; San Francisco, CA. Oral H-555 3. Cohen C, et al. HIV-11 2012; Glasgow. O425; Data on File
4. Rockstroh J, et al. IAC 2012; Washington, DC. LBPE019 5. Walmsley S, et al. ICAAC 2012; San Francisco, CA. Oral H-556b 6. Cohen C, et al. JAIDS 2012;60:33-42
Study 102/103 – Through Week 144 Renal Events Leading to Study Drug Discon=nua=on
Clumeck N, et al. 14th EACS; Brussels, Belgium; October 16-‐19, 2013. Abst. LBPS7/2. Wohl D, et al. ICAAC 2013. Denver, CO.#H-‐672a
Onset (Week)
STB – Study 102 (n=348)
0-‐24
Proximal Renal Tubulopathy
Isolated Rise in Crea=nine
Onset (Week)
STB – Study 103 (n=355)
0-‐24 24-‐48 48-‐96 96-‐144
Proximal Renal Tubulopathy 0 0 0 0
Isolated Rise in Crea=nine 2 (0.6%) +2 (0.6%) 0 +1 (0.3%)
48-‐96
+1 (0.3%)
0 2 (0.6%)
4 (1.1%)
24-‐48
0
0 +1 (0.3%)
0
96-‐144
1.Rockstroh JK, et al. HIV-‐11 2012; Glasgow. 0424 2.Rockstroh JK, et al. JAIDS 2013, e-‐published
Incidence/Prevalence of Common Gastrointes=nal AEs Study 102 – Week 144
STB (n=348) ATR (n=352)
Diarrhea Nausea
Weeks Weeks
Pa=en
ts with AE (%
)
6% 5% 4% 5%
4% 5% 4% 4%
48 96 144 48 96 144
4%
3%
7%
6%
Wohl D, et al. ICAAC 2013. Denver, CO.#H-‐672a
Taken from: Fischl M, et al. CROI 2000, Abstract 71
The evolu=on of ART: simpler, well tolerated regimens 1996
d4T+3TC+IDV 10 / Q8h
1998
AZT/3TC+EFV 5 / BID
2000
AZT/3TC/ABC 1 / BID
2003
TDF+FTC+EFV 3 / QD
2004
TDF/FTC+EFV
ABC/3TC+EFV
2 / QD
2006
TDF/FTC/EFV 1 / QD
2011
TDF/FTC/RPV 1 / QD
2012
TDF/FTC/EVG/Cobi 1 / QD
Hicks C, et al. EACS 2007. Madrid. Poster P5.7/01
Vera J, Aragão F. HIV11, Glasgow, UK 2012 #P5c
The Future: More ARVs, More FDCs and STRs
van Sighem A, et al. CROI 2010. Abstract 526
Stalemate? Or the Cure?
“…may HIV flow from our blood Into our history books..”
-‐ William Jefferson Clinton 10th Retrovirus Conf. Boston 2003