Transcript Prof R Gandhi - Update on ART Current Treatment Guidelinesx

Update on Antiretroviral Therapy:
Current Treatment Guidelines and
What’s on the Horizon
Where Do We Come From? What Are We? Where Are We Going?
– Paul Gauguin
Rajesh T. Gandhi, M.D.
Disclosures: grant support from Gilead, Roche, EBSCO
Thanks to Jacqueline Chu, M.D., Joe Eron, M.D. and Neha Patel for
assistance with slides
Updated: July 28, 2015
Updated: Sept. 2015
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
Case
• 55 yo M with HIV infection
• Past history: gastroesophageal reflux disease
(GERD), allergic rhinitis, hypertension, smoking,
elevated lipids
• Medications: fluticasone, omeprazole
• CD4 cell count 550. HIV RNA 125,000
• He asks 3 questions:
– “When should I be treated for HIV?”
– “What should l be treated with?”
– “If I take medicines, will I be cured?”
When to Start
START
Immediate ART (n=2326)
HIV-infected adults
CD4 count >500
Deferred ART (n=2359)
(CD4 Declined to <350 or AIDS-related
event)
• Enrolled 4685 pts from 35 countries
• Primary endpoint: serious AIDS-related event, serious non–
AIDS-related event, or death
• May 2015: DSMB recommended offering ART to all participants
• Median age: 36 yrs; mean follow-up 3 yrs.
• Median baseline CD4 count 651. Deferred group: median CD4
count at ART initiation, 408
Insight START Study Group, NEJM, 2015
START
• Primary endpoint: 57%
lower in immediate-ART
arm than in deferred arm
• Benefits of immediate
ART similar in all patient
subgroups, e.g. highincome and
low/moderate income
regions
• No increase in adverse
events associated with
immediate vs. deferred
ART
Time to primary event
Deferred initiation
Immediate
initiation
• 68% of primary endpoints
occurred in pts with CD4
>500
Insight START Study Group, NEJM, 2015
START: AIDS- and non-AIDS events
Number of Serious Events
100
Number of Events
80
96
Deferred ART (n=2359)
Immediate ART (n=2326)
57%
Reduction
(P<0.001)
60
50
42
40
72%
Reduction
(P<0.001)
47
39%
Reduction
(P=0.04)
29
20
0
14
Composite
Endpoint
AIDSNon-AIDS
Related
Related
Components
(Serious Events)
Lundgren J, et al. 8th IAS Conference. Vancouver, 2015. Abstract MOSY0301.
The INSIGHT START Study Group. N Engl J Med. 2015;July 20..
• TB, Kaposi sarcoma,
lymphoma — most
common AIDSrelated events — all
less frequent in
immediate-ART gp
• Cancer rates
(combining
AIDS/non-AIDS)
lower in immediateART gp
• Cardiovascular
disease rates similar
between 2 gps -- but
baseline risk low
Temprano
Severe HIV morbidity
• Similar benefit to early ART (compared to
WHO-guided deferred ART) seen in
randomized study performed in Cote d’Ivoire
(n=2056, 41% with CD4 count >500)
44% reduction
in risk with
early ART
Severe HIV morbidity: All cause mortality; AIDS-defining event; severe
bacterial infection, non-AIDS cancers
The TEMPRANO ANRS 12136 Study Group. N Engl J Med 2015
WHO on Sept 30, 2015: “Treat-all”
36.9
http://www.who.int/hiv/en/
“When should I start treatment?”
You should start now!
When to Start: July 2015
ART recommended for all HIV+ individuals,
regardless of CD4 cell count
CD4 Cell Count
• ≤ 350
• 350-500
• >500
Recommendation
AI
AI
AI
AI: strong recommendation, data from randomized clinical
trials
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents
in HIV-1-infected adults and adolescents – updated
US DHHS Guidelines, January 2011.
July 28, 2015.
WHO: When to Start ART
Population
Adults
(>19 yr)
Recommendation
Children
Evidence
Initiate in All
Strong
Moderate
Priority: advanced clinical
disease, CD4 ≤350
Strong
Moderate
Strong
Moderate
Pregnant/breastInitiate in All
feeding women
Adolescents
(10–19 yo)
Strength
Initiate in All
Conditional Low
Priority: advanced clinical
disease, CD4 ≤350
Strong
Moderate
Initiate in All
1-10 yo:
Conditional
<2 yo:
Strong
1-10 yo:
Low
<2 yo:
Moderate
WHO Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV, Sept 2015
When to Start ART after Opportunistic
Infection (OI)
OI
When to start
Cryptosporidiosis,
microsporidiosis, PML
As part of initial therapy of the OI
PCP, MAC,
Toxoplasma, most
other OIs
Within 2 weeks
Tuberculosis
If CD4 count <50: within 2 wk
If CD4 count >50: within 8-12 wks
(TB meningitis: careful
monitoring/consultation)
Cryptococcal
meningitis
4-5 weeks after initiation of anti-fungal
therapy
Zolopa A et al, PLoS One. 2009; Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected
Adults and Adolescents, 2013, WHO Consolidated ARV Guidelines, 2013. Zanoni and Gandhi, Inf Dis Clin N Am, 2014
“How should I be treated?”
What to Start
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
13
Case – What to Start?
• 55 yo M with HIV
• GERD, allergic rhinitis, HTN, smoking,
elevated lipids. Medications: fluticasone,
omeprazole
• CD4 cell count 550. HIV RNA 125,000
Reproductive Cycle of HIV and Sites of Action of
Major Classes of Antiretroviral Medications
Gandhi M, Gandhi RT. N Engl J Med 2014;371:248-259.
Reproductive Cycle of HIV and Sites of Action of
Major Classes of Antiretroviral Medications
Fusion Inhibitors
CCR5 Antagonists
Reverse Transcriptase
Inhibitors (RTI)
Nucleoside RTI (NRTIs) –
tenofovir, abacavir, 3TC
Protease inhibitors (PI) –
lopinavir/ritonavir
Integrase strand transfer
inhibitors (INSTI) –
Nonnucleoside RTI
dolutegravir, raltegravir,
(NNRTIs) -- efavirenz
elvitegravir/cobicistat
Gandhi M, Gandhi RT. N Engl J Med 2014;371:248-259.
What to Start – 2015
Recommended Regimens (n=5)
Dolutegravir/abacavir/3TC
Integrase inhibitor + Dolutegravir + tenofovir/FTC
2 Nucleoside RTI
Elvitegravir/cobi/Tenofovir/FTC
Raltegravir +Tenofovir/FTC
Protease inhibitor +
Darunavir/ritonavir +TDF/FTC
2 Nucleoside RTI
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
WHO: What to Start
Recommended Regimens
Non-nucleoside RTI +
2 Nucleoside RTI
TDF + (3TC or FTC) +
Efavirenz (EFV)
In the U.S. Guidelines, EFV/TDF/FTC
Moved to Alternative
• EFV: long track record
but, compared with new
regimens, decreased
tolerability
– In SINGLE trial, DTG
+ ABC/3TC superior
to EFV/TDF/FTC,
largely because of
more treatment
discontinuations in
EFV gp (10% vs. 2%)
Walmsley S et al, NEJM, 2013
DTG + ABC/3TC vs. EFV/TDF/FTC
Efavirenz and Suicidality
0.05
EFV
EFV-free
0.04
Probability
• In retrospective analysis of
multiple ACTG studies1,
increased suicidality in
those randomized to EFVcontaining regimens as
compared to EFV-free
regimens
• In a genetic substudy2,
those predicted to have
slowest clearance of EFV
had highest relative risk of
suicidality
HR: 2.28
(95% CI 1.27-4.10; P = .006)
0.03
0.02
47 events/5817
PY (8.1/1000 PY)
0.01
15 events/4099
PY (3.66/1000 PY)
0
0
24
48
72
96 120 144 168 192
Wks to Suicidality
1Mollan
2Mollan
K et al, Ann Int Med, 2014
KR et al, IAS 2015 TUPEB273
Integrase Inhibitors for 1st Line HIV
Therapy
• Elvitegravir/cobi superior to
atazanavir/ritonavir (PI) in HIV+ women
(WAVES)
• Raltegravir superior to atazanavir/ritonavir
and darunavir/ritonavir (ACTG A5257)
• Dolutegravir superior to darunavir/ritonavir
(FLAMINGO)
• Dolutegravir superior to efavirenz (SINGLE)
In U.S. guidelines, 4 of 5 recommended options
for initial therapy include integrase inhibitor
Is Efavirenz 400 the Answer?
• ENCORE 1: EFV 400 mg vs. EFV 600 mg each
in combination with TDF/FTC
- EFV 400 non-inferior to EFV 600 mg
- ≈90% virologic suppression in both arms
- Fewer participants in 400 mg group had
EFV-related side effects
• Studies of EFV 400 in pregnant women and with
TB treatment (rifampicin)
• Randomized trial to compare TDF/3TC/EFV 400
to TDF/3TC/DTG (NAMSAL)
Encore 1 Study Group, Lancet ID, 2015
Choosing an Antiretroviral Regimen
• Patient-related considerations:
- HBV coinfected: choose TDF + 3TC or FTC
- Cardiovascular disease: Favor tenofovir over
abacavir
- Renal disease: Favor abacavir over tenofovir
• Drug-related considerations:
- Food: efavirenz best on empty stomach
- Drug interactions: protease inhibitors (and
cobicistat) inhibit CYP3A4  many
interactions
Drug Interactions: Exogenous Steroids
• Injectable steroids: levels increased by PIs
– 10% of patients on PIs who received a steroid
injection developed clinical evidence of steroid
excess or adrenal insufficiency1
• Inhaled fluticasone2 & budesonide3: systemic
levels increased by PIs
– Beclomethasone is a safer alternative4
1Hyle
2DHHS
E et al, JAIDS, 2013
guidelines for use of antiretroviral agents in HIV-1-infected adults and adolescents. Feb 12, 2013.
http://AIDSinfo.nih.gov
3http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm336367.htm
4Boyd
S et al, JAIDS, 2013
Case: Salient Considerations
• 55 yo M with HIV. Genotype: no resistance.
• Choosing the NRTIs:
– High risk for CV disease (HTN, smoking)
– Elevated lipids
 Favor TDF/FTC
• Choosing between NNRTI, PI, INSTI:
– High VL (>100,000) – don’t choose rilpivirine (RPV)
– On omeprazole – reduces ATV, RPV absorption
– On fluticasone – interacts with PIs, cobi
 Favor Dolutegravir
ART: On the Horizon
Reproductive Cycle of HIV and Sites of Action of
Major Classes of Antiretroviral Medications
Fusion Inhibitors
CCR5 Antagonists
Reverse Transcriptase
Inhibitors (RTI)
Protease inhibitors (PI)
Nucleoside RTI (NRTIs) –
TAF
Nonnucleoside RTI
(NNRTIs) –Long-acting
Integrase strand transfer
inhibitors (INSTI) – long-
Rilpivirine;Doravirine,
acting Cabotegravir
Gandhi M, Gandhi RT. N Engl J Med 2014;371:248-259.
New version of current medication:
Tenofovir alafenamide (TAF)
• TAF: pro-drug of tenofovir that concentrates in cells,
converted to tenofovir (TFV)
• TAF: 90% lower plasma TFV levels compared to TDF
(tenofovir disoproxil fumarate)
• TAF compared to TDF for initial therapy:
n=1733
Sax P et al, Lancet, 2015
TAF vs. TDF
HIV-1 RNA <50 c/mL, %
100
92 90
• Virologic efficacy: E/C/F/TAF
non-inferior to E/C/F/TDF
E/C/F/TAF
80
E/C/F/TDF
60
40
20
4
4
4
6
0
Success
Failure
Sax P et al, Lancet, 2015.
No Data
• TAF associated with:
• Smaller decrease in bone
mineral density (BMD)
• Smaller decrease in eGFR
• Less proteinuria
• Greater increases in
cholesterol, LDL, HDL,
TGs (identical changes in
TC:HDL)
TAF Switch Studies
Median % Change
in Spine BMD (Q1, Q3)
• In switch studies, changing from TDF to TAF:
• Similar or higher virologic efficacy
• Stable/improved renal function; less proteinuria
• Increased bone mineral density:
4
3
2
1
0
-1
-2
-3
Baseline
EVG/COBI/FTC/TAF
TDF-based regimen
1.79
-0.28
Wk 24
Wk 48
Mills A, et al. IAS 2015. # TUAB0102; Gupta S, et al. IAS 2015. # TUAB0103; Gupta S
et al, ICAAC, 2015; Shamblaw D et al, ICAAC 2015; Thompson M et al, IDWeek 2015
Switch to E/C/F/TAF in Patients With
Renal Impairment (Study 112)
Treatment-experienced
HIV RNA <50
eGFR 30-69
Switch to E/C/F/TAF (open-label)
(n=242)
Primary Endpoint
Wk 24: Change From
Baseline in eGFR
• Median age: 58. Median eGFR 56. HTN 40%; DM:
14%. 65% on TDF prior to switch
• GFR unaffected by switch to E/C/F/TAF
• After switch to E/C/F/TAF, improved:
– Spine and hip BMD
– Albuminuria and proteinuria
Gupta S, et al. J Int AIDS Soc. 2015;18(suppl 4):35-36. IAS 2015 Abstract TUAB0103
Switch to E/C/F/TAF in HIV/HBV
Coinfected Patients (Study 1249)
HIV+/HBsAg positive
HBV DNA <9 log10 IU/L
HIV RNA <50
Switch
to E/C/F/TAF
Switch to E/C/F/TAF
(n=72)
(n=242)
Primary Endpoint Wk 24: HIV RNA <50; HBV DNA <29 IU/mL
Wk 48
• Pre-switch: 96% on TDF; 42%
HBeAg+
• Following switch to E/C/F/TAF:
– HIV suppression maintained
– HBV suppression maintained
– No HBV flares
100
100
92
92
80
62
60
5
40
20
0
HIV-1 RNA
<50c/mL
Gallant J, et al. 8th IAS Conference. Vancouver, 2015. Abstract WELBPE13.
86
HBV DNA<29
IU/mL
Fibrosis
(mod/seve
Elvitegravir/cobicistat/FTC/TAF –
Approved in U.S. on Nov. 5, 2015
FTC/TAF – April 2016
Rilpivirine/FTC/TAF – July 2016
Darunavir/cobi/FTC/TAF – phase III
DTG/FTC/TDF vs. DTG/FTC/TAF in
treatment naïve pts– WITS RHI
On the Horizon: Nuc-lite or Nuc-sparing regimens
• For initial therapy
– LPV/r + 3TC; GARDEL
– DRV/r + RAL; NEAT001
– DTG + 3TC3 – being studied (PADDLE, ACTG 5353)
• Switching after patient virologically suppressed
(maintenance therapy)
– Switch to LPV/r + 3TC/FTC (OLE)
– Switch to ATV/r + 3TC (SALT)
– DTG + 3TC3 (ASPIRE) – being studied
– DTG/RPV – being studied (SWORD-1 and -2)
Cahn, Lancet ID 2014; Gatell, Lancet ID 2015; Perez-Molina, Lancet ID 2015. 2. Raffi, Lancet 2014; Boyd Lancet 2013. 3. Girouard, IAS 2015 TULBPE12; PADDLE,
ASPIRE, ACTG A5353
ART: Long-acting Agents
• Long-acting agents:
cabotegravir, LArilpivirine, broadlyneutralizing antibodies
• Cabotegravir (CBG)
and rilpivirine (RPV)
available in long-acting
nanosuspension
formulations which
have half-lives of
months
Latte-2
At wk 32, VL <50 in 95% of q8 wk
arm, 94% of q4 wk arm, 91% of oral
arm. Only 1 pt in an injection arm
had virologic failure: no resistance.
Spreen, JAIDS 2014; Margolis CROI 2015 #554LB; Jackson, Clin Pharmacol Ther 2014; Caskey, Nature 2015, Viiv press release, Nov 2015
New Drugs in New Classes
Fusion Inhibitors
CCR5 Antagonists
Reverse Transcriptase
Inhibitors (RTI)
Protease inhibitors (PI)
Nucleoside RTI (NRTIs)
Nonnucleoside RTI
(NNRTIs)
Integrase strand transfer
inhibitors (INSTI)
Gandhi M, Gandhi RT. N Engl J Med 2014;371:248-259.
New Drugs in New Classes
Fusion Inhibitors
CCR5 Antagonists
Attachment inhibitor:
BMS-663068 (prodrug)
Promising phase IIb
results (n=251)
Maturation inhibitor:
BMS 955176: phase IIb
(with DTG + ATV +/RTV) in treatmentexperienced pts
Phase 3 trial of 068* +
GSK2838232 (phase I)
optimized background
Reverse Transcriptase
therapy vs. OBT in
Inhibitors (RTI)
treatment experienced
Protease inhibitors (PI)
Nucleoside RTI (NRTIs)
pts with multidrug
Integrase strand transfer
Nonnucleoside RTI resistant HIV
(NNRTIs)
*600 mg bid
inhibitors (INSTI)
Gandhi M, Gandhi RT. N Engl J Med 2014;371:248-259.
Hwang et al, IAS 2015, TUAB0106LB, Jeffrey et al, CROI 2015 538; Lataillade, IAS 2015 TUPEB284; Lalezari Lancet HIV, 2015
Challenges and Opportunities
• Ending the
epidemic with
ART?
--90/90/90
• Cure?
Ending the Epidemic with ART?
• Treatment and virologic suppression markedly reduce
transmission1,2 (“Treatment as prevention”)
• Modeling suggests that treating a high proportion of
infected patients could end the epidemic by 20303
• UNAIDS Treatment Targets:
= 73%
suppressed
1. Cohen MS, et al. N Engl J Med 2011;10.1056. 2. Cohen MS, et al. IAS 2015, MOAC0101LB. 3. UNAIDS, 2014
In which country is the highest
proportion of HIV-infected patients
virologically suppressed?
A.
B.
C.
D.
E.
U.S.
Russia
Britain
Rwanda
Switzerland
Percentage of HIV+ People with
HIV RNA Suppression
100%
90%
80%
70%
UNAIDS Target:
73% of all HIV+ people
achieving viral
suppression
68%
62%
61%
60%
59%
52%
52%
50%
40%
40%
35%
32%
30%
30%
30%
20%
9%
10%
0%
Switzerland Australia
<200
<400
United
Kingdom
<200
Denmark
<500
Rwanda
<40
France <50
Brazil
<1000
= Regional average
Adapted from Levi J, et al. IAS 2015. MOAD0102.(*SSA
From 30 countries)
British
Sub
Columbia Saharan
(Canada) Africa <400
<50
to <40
Cuba
USA <200
Russia
<1000
Case
• 55 yo M with HIV infection
• “If I take medicines, will I be cured?”
• Only 1 known case of HIV cure:
– HIV+ man with leukemia who underwent allogeneic
stem cell transplant with a CCRdelta32
homozygous bone marrow
– Following the transplant, he stopped ART and has
remained without any evidence for infection
Why Should We Try to Cure HIV?
• Although life expectancy has improved, HIV+
patients, especially if diagnosed late, don’t live as
long as HIV-negative people -- perhaps because
of persistent inflammation in HIV+ patients
• Cost, side effects, and impact on quality of life of
life-long ART
• Need to maintain high level of adherence to ART
to prevent drug-resistant virus
• Stigma, discrimination, fear of transmission,
isolation
Adapted from slide
by Joe Eron, MD
“If I take medicines, will I be cured?”
Why does ART not Cure HIV?
Long-lived latent reservoir
Frequency of Latently Infected CD4+
T Cells as a Function of Time on HAART
10000
t ½ = 44.2 months
73.4 years
Frequency
(IUPM)
1000
100
10
1
0.1
-
0.01
0.001
0.0001
0.00001
0
1
2
3
4
5
6
Time on HAART (years)
Siliciano J, Nature Medicine, 2003
7
8
Persistent HIV Production Despite ART
Using extremely sensitive assays, plasma viremia
detectable in most patients on ART, often below the
detection limit of commercial assays (<20 copies/mL)
Treatment intensification?
100 copies
50 copies
10 copies
1 copy
Maldarelli F, et al. PLoS Pathog. 2007;3:e46.
Adding 4th Drug (raltegravir) to 3-drug ART
does not reduce low-level viremia
No RAL
+RAL
No RAL
♦ Arm A: RAL first (immediate intensification)
● Arm B: Placebo first (deferred intensification)
Gandhi R et al, PLoS Med, 2010
Can we cure HIV?
“It's tough to make predictions, especially
about the future”
Can we cure HIV? “ART-Plus”
• HIV cure remains an aspirational goal
• Clinical trials are testing ways to:
• Reverse latency
• Enhance killing of infected cells
• Make cells impervious to infection
• Combination therapy!!
• Increased knowledge of mechanisms of HIV
persistence needed
• Given safety of current ART and uncertainties
regarding risks of novel interventions, cure
studies must adhere to highest scientific and
ethical standards
World AIDS Day, 2013:
. . . the United States should be at the forefront of
new discoveries into how to put HIV into long-term
remission without requiring lifelong therapies -- or,
better yet, to eliminate it completely.
Patient: One day I’d love to say, “I used to have HIV.”